Potassium Phosphate-Catalyzed Chemoselective Reduction of α-Keto Amides: Route to Synthesize Passerini Adducts and 3-Phenyloxindoles

Article abstract of DOI:10.1002/adsc.201500815

A chemoselective reduction of α-keto amides to biologically important α-hydroxy amides (mandelamides) by polymethylhydrosiloxane (PMHS) using 5 mol% potassium phosphate (K₃PO₄) as catalyst has been developed. This transition metal-free protocol discloses excellent chemoselectivity for the ketone reduction of α-keto amides in the presence of other reducible functionalities like ketone, nitro, halides, nitrile and amide. Also, the chemoselectively reduced α-hydroxy amide has been derivatized to isocyanide-free Passerini adducts. The N-alkyl-α-hydroxy amides have been successfully converted to 3-phenyloxindole derivatives by treatment with methanesulfonyl cholride and triethylamine.

Full text of DOI:10.1002/adsc.201500815

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DOI: 10.1002/adsc.201500815
Potassium Phosphate-Catalyzed Chemoselective Reduction of
a-Keto Amides: Route to Synthesize Passerini Adducts and
3-Phenyloxindoles
Alagesan Muthukumar,a N. Chary Mamillapalli,a and Govindasamy Sekara,*
a
Department of Chemistry, Indian Institute of Technology Madras, Chennai – 600036, India
Fax: (+91)-44-2257-4202; phone: (+91)-44-2257-4229; e-mail: gsekar@iitm.ac.in
Received: September 2, 2015; Revised: November 20, 2015; Published online: February 8, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500815.
Abstract: A chemoselective reduction of a-keto duced a-hydroxy amide has been derivatized to isocy-
amides to biologically important a-hydroxy amides anide-free Passerini adducts. The N-alkyl-a-hydroxy
(mandelamides) by polymethylhydrosiloxane (PMHS) amides have been successfully converted to 3-phenyl-
using 5 mol% potassium phosphate (K3PO4) as cata- oxindole derivatives by treatment with methanesul-
lyst has been developed. This transition metal-free fonyl cholride and triethylamine.
protocol discloses excellent chemoselectivity for the
ketone reduction of a-keto amides in the presence of Keywords: chemoselective reduction; metal and
other reducible functionalities like ketone, nitro, hal- ligand free; Passerini adducts; 3-phenyloxindoles;
ides, nitrile and amide. Also, the chemoselectively re- phosphate catalyst
Introduction
a-Hydroxy amides (mandelamides) are one of the
most enchanting structural classes, as they exhibit me-
dicinal and pesticidal properties.[1–3] In addition, they
can act as ligands due to the existence of hydroxy and
amide groups with variable coordinating abilities.[4]
Altering the oxidation states of carbonyl functionali-
ties is one of the most important transformations in
organic chemistry.[5,6] Among them, reduction of car-
bonyl groups is always of crucial importance.[7] How-
ever, the chemoselective reduction of carbonyls over
other sensitive groups at room temperature is invaria-
bly a challenging task as it is one of the key factors of
modern synthetic methodologies. Until recently, the
progress of most chemoselective reductions of carbon-
yls was based on transition metal catalysts.[8] Hence,
a main goal in the carbonyl reduction is the develop-
ment of new and easily available transition metal-free
catalysts, which offer economic as well as ecological
benefits.[9] In this context, metal-free reduction of
simple carbonyls are reported with bases such as alk-
oxide,[10] hydroxide,[11] carbonate[12] and fluoride[13] as
catalysts. However, base-catalyzed chemoselective re-
duction of carbonyls is not that well explored.
Recently, we developed the chemoselective reduc-
Scheme 1. Chemoselective reduction of a-keto amide by
K3PO4 catalyst; retrosynthetic approach towards Passerini
tion of a-keto amides using Ni-TMEDA catalyst
(Scheme 1).[14] Then, we have developed the metal- adducts and 3-phenyloxindole via a-hydroxy amide.
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Table 1. Optimization for the chemoselective reduction of 1a.[a]
[a]
Reaction conditions: 0.5 mmol of 1a in 1.5 mL of solvent.
Isolated yield.
In the absence of K3PO4.
[b]
[c]
free chemoselective reduction of a-keto amides using ties for organic transformations.[17] Only a handful ex-
TBAF as catalyst.[15] Although efficient catalytic sys- amples are known for its catalytic activity.[18]
tems for the reduction of a-keto amides have been
developed, our focus is shifted towards the develop-
ment of more efficient catalytic systems to overcome Results and Discussion
the shortcomings such as need of inert atmosphere,
loss of chemoselectivity and use of expensive Ph3SiH The initial optimization for the chemoselective reduc-
which gives high molecular weight by-products, etc. tion was carried out with 2-oxo-N-2-diphenylaceta-
As part of our research towards developing metal- mide 1a as model substrate, using 2 equivalents of low
free organic transformations,[16] herein we report cost, non-toxic, air-stable and eco-friendly polyme-
a mild, efficient and economic chemoselective reduc- thylhydrosiloxane (PMHS)[19] as reducing agent and
tion of the keto group of a-keto amides in the pres- 10 mol% of K3PO4 as catalyst at room temperature in
ence of reducible functional groups using K3PO4 as dichloromethane. The reaction yielded 63% of the se-
catalyst (Scheme 1). To show the utility of mandel- lective reduction product a-hydroxy amide 2a and
amide, a retrosynthetic approach towards highly im- 18% of complete reduction (both keto and amide
portant Passerini adducts and 3-phenyloxindoles from groups) product N-phenylphenylethanolamine 3a in
a-keto amides is given. Albeit K3PO4 is an inexpen- 8 h (Table 1, entry 1). Use of a non-polar hydrocarbon
sive base, it is typically used in stoichiometric quanti- solvent, for instance, toluene gave exclusively 2a in
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Potassium Phosphate-Catalyzed Chemoselective Reduction of a-Keto Amides
Table 2. Scope of substrates for the chemoselective reduction of a-keto amides using K3PO4 catalyst.[a,b]
[a]
Reaction conditions: 0.5 mmol of 1 in 1.5 mL of 1,4-dioxane.
Isolated yield.
10 mol% of K3PO4 was used and reaction was carried out at 608C.
21% of 2o was isolated along with 2n.
10 mol% of K3PO4 and 5.0 equiv. of PMHS were used.
20 mol% of K3PO4 and 4 equiv. of PMHS were used at 608C.
[b]
[c]
[d]
[e]
[f]
23 h with 86% isolated yield (entry 2). When the sol- are summarized in Table 1. The silanes (EtO)3SiH,
vent was altered to THF, a drastic upturn in the reac- ClSi(CH3)2 H, Cl2(CH3)SiH and Ph3SiH did not afford
tivity was observed but the selectivity got diminished complete conversion of starting material 1a to a-hy-
as it yielded 82% of 2a along with 10% of 3a in droxy amide 2a even after 48 h (entries 7–10). When
45 min (entry 3). The polar protic solvent methanol Ph2SiH2 was used, 58% of 2a was isolated along with
provided only 46% of 2a even after two days unidentified side products (entry 11). In the case of
(entry 4). When 1,4-dioxane was used, the reaction tetramethyldisiloxane (TMDSO), 92% of 2a was iso-
was completed in 45 min with 91% of 2a and a trace lated (entry 12). It is important to mention that
amount of 3a (entry 5). From this study of solvent ef- screening of other phosphate bases such as K2HPO4,
fects, it is understood that polar aprotic solvents are KH2PO4, Na2HPO4 and NaH2PO4 did not afford 2a
appropriate for this transformation.
(entries 13–16). As anticipated, there was no reaction
Next, the amount of catalyst loading was reduced in the absence of K3PO4 (entry 17).
to 5 mol% and the reaction was performed in 1,4-di-
With the optimized conditions in hand (Table 1,
oxane. It yielded exclusively the selective reduction entry 6), the scope of the chemoselective reduction
product 2a with 97% yield in 2 h (entry 6). However, protocol was investigated with several a-keto amides
the derivative of THF such as 2-methyl-THF a “green- and the results are summarized in Table 2. Both elec-
er” solvent furnished 63% of 2a and 11% of 3a tron-releasing and electron-withdrawing groups at-
(entry 18). In order to understand the chemoselectivi- tached to either side of the a-keto amide furnished
ty, various hydrosilanes were examined and the results the corresponding a-hydroxy amides in good to excel-
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lent yield. It is vital to mention that other sensitive
functional groups prone to reduction such as nitro
(2h), chloro (2i and 2j) and nitrile (2k) were unaffect-
ed under the reaction conditions. The 1-naphthyl-
amine-derived a-keto amide yielded 97% of the re-
spective a-hydroxy amide (2f).
The methodology worked well for the reduction of
a-keto amide bearing an amide group para to the ani-
lide ring to the a-hydroxy amide (2l) in 93% yield
without affecting both amide groups using 10 mol%
of K3PO4 at 608C. This is due to the insoluble nature
of the a-keto amide at room temperature. Important-
ly, a-keto benzylamide failed to render the mandela-
mide (2m). Hence, to distinguish the chemoselective
ketone reduction of a-keto anilide over a-keto benzy-
lamide, the 4-(aminomethyl)aniline derived di-a-keto
Scheme 2. Intermolecular competitive reduction experi-
ments between 1a and simple ketones.
amide was examined under the defined conditions. In- sively without affecting the isolated ketones
terestingly, both mono keto reduced a-hydroxy amide (Scheme 3).
(2n) and the diketo reduced di-a-hydroxy amide (2o)
To examine the scalability of the metal free trans-
were isolated in 73% and 21% yield, respectively. In formation, the chemoselective reduction of 2-oxo-N-
addition, a set of conditions was achieved to attain 2-diphenylacetamide 1a was performed by employing
only di-a-hydroxyamide (2o) in 96% yield by increas- 1 gram (4.4 mmol) of 1a under the standard reaction
ing the catalyst amount to 10 mol% and PMHS to conditions. This transformation proceeded well to
5 equivalents.
A
2-pyridyl group bearing a-keto afford a-hydroxy amide 2a in 92% yield (Scheme 4).
amide rendered the corresponding product (2p) in ex-
The a-hydroxy amide 2a was successfully converted
cellent yield. N-Substituted a-keto amides furnished to synthetically and biologically important O-acylated
the mandelamide analogues (2q and 2r) in moderate (7), arylated (8), silylated (9) and alkylated (10) Pass-
to good yield. In addition, a few substituted a-keto erini adducts,[20a] respectively. Although it involves
benzylamides were examined under the optimized two more steps, noxious, bad smelling and expensive
conditions. None of them gave the corresponding isocyanides[20b] can be avoided through this pathway
products. But trace amounts of products (2s and 2t)
were identified when the amount of K3PO4 was in-
creased to 20 mol% and PMHS to 4 equivalents. Re-
actions at 608C with 20 mol% of K3PO4 and 4 equiva-
lents of PMHS resulted in 22% of 2s and 18% of 2t.
Further increases in temperature did not improve the
reaction yield. The a-keto amides derived from ben-
zylamine and 1-phenylethaneamine did not afford the
reduced products (2m and 2u) even if K3PO4, PMHS
and temperature were increased. Also, the aliphatic
amines derived a-keto amides did not yield the corre-
sponding mandelamides.
To show the utility of this protocol, an intermolecu-
lar competitive reduction experiment between a-ke-
toamide (1a) and simple ketones (3) like acetophe-
none or benzophenone was carried out under the de-
fined conditions. The chemoselectivity of these reduc-
tion reactions was perfect and a-hydroxy amide (2a)
was obtained as the exclusive product along with 3 as
Scheme 3. Chemoselective reduction of a-keto amide versus
simple ketone. Reaction conditions: 0.5 mmol of 5 in 1.5 mL
of 1,4-dioxane; isolated yields given.
intact starting materials (Scheme 2). This displays that
the reaction is mild and precise for the chemoselec-
tive reduction of a-keto amides.
The usefulness of the competitive experiment was
further studied with the a-keto amides (5a–5c) bear-
ing isolated ketones under the defined conditions.
The keto functionality of a-keto amides got reduced
to the corresponding a-hydroxy amides (6a–6c) exclu- Scheme 4. Gram-scale synthesis of 2a.
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Potassium Phosphate-Catalyzed Chemoselective Reduction of a-Keto Amides
Scheme 5. Derivitization of 2a to isocyanide-free Passerini adducts
Scheme 6. Isocyanide-free one-pot synthesis of O-acylated
Passerini adduct 7
Scheme 8. Plausible mechanism for phosphate-catalyzed
chemoselective reduction of a-keto amides.
phate-promoted chemoselective reduction of a-keto
amides using PMHS has been proposed (Scheme 8).
Initially, phosphate anion I may interact with PMHS
to give hypervalent silyl-phosphate ester II.[23] This
further reacts with a-keto amide 1 via the transfer of
Scheme 7. Synthesis of N-alkyl-3-phenyloxindoles from man-
delamides
in short reaction times and good to excellent yields hydride to activated ketone to form O-silyl ether IV
(Scheme 5). by discharging the phosphate ion I. Hydrolysis of IV
We also succeeded to synthesize the O-acylated provides a-hydroxy amide 2. However, detailed
Passerini adduct (7) by a one-pot synthesis involving mechanistic studies and further applications of this
reduction of 1a followed by acylation using acetyl chemoselective reduction are in progress.
chloride in 52% isolated yield (Scheme 6).
The N-alkyl-a-hydroxy amides (2q and 2r) were
further converted in good yield to highly important Conclusions
N-alkyl-3-phenyloxindoles[21] (11q and 11r) by treat-
ment with methanesulfonyl chloride and triethyla- In summary, we have established a mild, efficient,
mine (Scheme 7). Although several ways are possible transition metal- and ligand-free chemoselective re-
to synthesize 3-phenyloxindoles,[22] this method repre- duction of a-keto amides to a-hydroxy amides by in-
sents one of the most easily accomplished ways to expensive, air stable and eco-friendly PMHS using
access them.
K3PO4 as catalyst at room temperature. The metal-
Based on the base-catalyzed, hydrosilane-mediated free protocol has several advantages including cost-ef-
reductions,[10–13] a plausible mechanism for this phos- fectiveness, short reaction time, high yield and room
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mixture was extracted with ethyl acetate (2”10 mL). The
combined organic layers were washed with brine, dried over
anhydrous MgSO4, filtered off and the solvent was removed
under reduced pressure. The resulting residue was purified
by silica gel column chromatography (eluent: hexanes-ethyl
acetate, 80:20) to obtain the pure a-hydroxyamide.
temperature reaction. More importantly, the other re-
ducible functionalities such as ketone, nitro, halides,
nitrile and amide are well tolerated. To show the im-
portance of this methodology, several Passerini ad-
ducts have been synthesized from a-hydroxy amides
by avoiding harmful isocyanides. Also, N-alkyl-a-hy-
droxy amides have been easily converted to 3-phenyl-
oxindole derivatives in a single step process.
2-Hydroxy-N,2-diphenylacetamide (2a):[24] Colourless
solid; mp 151–1528C (Lit.[24] mp 150–1518C); Rf =0.54 (hex-
1
anes:ethyl acetate, 80:20 v/v); H NMR (500 MHz, CDCl3):
d=8.18 (bs, 1H), 7.43–7.56 (m, 4H), 7.28–7.42 (m, 5H), 7.12
(t, J=7.0 Hz, 1H), 5.17 (s, 1H); 13C NMR (125 MHz,
CDCl3): d=170.1, 139.1,137.2, 129.2, 129.1, 129.0, 127.0,
124.9, 120.0, 74.9; IR (KBr): n=3302, 1685, 1653, 1648,
1077 cmÀ1; HR-MS: m/z=250.0852 [M+Na]+, calcd. for
C14H13NO2Na1: 250.0844.
2-Hydroxy-2-(4-methoxyphenyl)-N-phenylacetamide
(2b):[14] Colourless solid; mp 95–968C (Lit.[14] mp 94–958C);
Rf =0.32 (hexanes:ethyl acetate, 80:20 v/v); 1H NMR
(500 MHz, CDCl3): d=8.24 (bs, 1H), 7.51 (d, J=7.5 Hz,
2H), 7.36 (d, J=8.5 Hz, 2H), 7.30 (t, J=7.5 Hz, 2H), 7.11
(t, J=7.5 Hz, 1H), 6.89 (d, J=8.5 Hz, 2H), 5.09 (s, 1H),
3.79 (s, 3H); 13C NMR(125 MHz, CDCl3): d=170.5, 160.1,
137.2, 131.3, 129.2, 128.4, 124.8, 119.9, 114.5, 74.4, 55.4; IR
(KBr): n=3366, 1670, 1598, 1534, 1444, 1077 cmÀ1; HR-MS:
m/z=280.0939 [M+Na]+, calcd. for C15H15NO3Na1:
280.0950.
2-Hydroxy-N-(4-methoxyphenyl)-2-phenylacetamide
(2c):[25] Colourless solid; mp 153–1548C (Lit.[25] mp 153–
1548C); Rf =0.34 (hexanes:ethyl acetate, 80:20 v/v);
1H NMR (400 MHz, DMSO-d6): d=9.78 (s, 1H), 7.59 (dd,
J=7.2, 2.0 Hz, 2H), 7.50 (d, J=7.2 Hz, 2H) 7.25–7.39 (m,
3H), 6.86 (d, J=6.8 Hz, 2H), 6.38 (d, J=4.8 Hz, 1H), 5.07
(d, J=4.4 Hz, 1H), 3.70 (s, 3H); 13C NMR (100 MHz,
DMSO-d6): d=170.7, 155.4, 141.0, 131.7, 128.1, 127.6, 126.6,
121.2, 113.7, 73.9, 55.1; IR (KBr): n=3651, 1647, 1559, 1540,
1534, 1090 cmÀ1; HR-MS: m/z=280.0945 [M+Na]+, calcd.
for C15H15NO3Na1: 280.0950.
Experimental Section
General Considerations
Hydrosilanes and K3PO4 were purchased from Sigma–Al-
drich and Alfa Aesar chemical companies, respectively.
Thin-layer chromatography (TLC) was performed using
Merck silica gel 60 F254 pre-coated plates (0.25 mm) and vi-
sualized by UV fluorescence quenching. Silica gel for
column chromatography (100–200 mesh) was purchased
1
from SRL India. H and 13C NMR spectra were recorded on
1
a Bruker 400 or 500 MHz instrument. H NMR spectra are
reported relative to residual CHCl3 (d=7.26 ppm) or
DMSO-d6 (d=2.50 ppm). 13C NMR are reported relative to
CDCl3 (d=77.16 ppm) or DMSO-d6 (d=39.52 ppm). FT-IR
spectra were recorded on a JASCO spectrometer and are re-
ported in frequency of absorption (cmÀ1). High resolution
mass spectra (HR-MS) were recorded on Q-Tof Micro mass
spectrometer.
General Experimental Procedure for Synthesis of a-
Keto Amides
Thionyl chloride (4 mmol) was added dropwise to a stirred
mixture of benzoylformic acid (2 mmol) and Et3N (4 mmol)
in CH2Cl2 (10 mL) at 08C under a nitrogen atmosphere. The
stirring was continued for 20 min and then a suspension of
the corresponding amine (2 mmol) in CH2Cl2 (10 mL) was
added slowly to the reaction mixture at 08C under a nitrogen
atmosphere. The stirring was continued at room tempera-
ture and the completion of the reaction was monitored by
TLC. The organic layer was washed with water for two
2-Hydroxy-2-phenyl-N-p-tolylacetamide (2d):[26] Colour-
less solid; mp 167–1688C (Lit.[26] mp 169–1708C); Rf =0.44
(hexanes:ethyl acetate, 70:30 v/v); 1H NMR (400 MHz,
DMSO-d6): d=9.80 (bs, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.50
(d, J=7.2 Hz, 2H), 7.25–7.39 (m, 3H), 7.08 (d, J=8.4 Hz,
2H), 6.39 (d, J=4.4 Hz, 1H), 5.08 (d, J=4.8 Hz 1H), 2.23
(s, 3H); 13C NMR (100 MHz, DMSO-d6): d=170.9, 140.9,
136.0, 132.4, 129.0, 128.1, 127.6, 126.6, 119.7, 74.0, 20.4; IR
(KBr): n=3412, 1522, 1437, 1364 cmÀ1; HR-MS: m/z=
264.0989 [M+Na]+, calcd. for C15H15N1O2Na1: 264.1000.
N-(2,6-Dimethylphenyl)-2-hydroxy-2-phenylacetamide
(2e): Colourless solid; mp 140–1418C; Rf =0.48 (hexane-
times, then
a saturated aqueous solution of NaHCO3
(20 mL) was slowly added to the reaction mixture. The or-
ganic layer was separated, washed with water (3”15 mL)
and evaporated under reduced pressure. The solid residue
was purified by silica gel column chromatography.
General Experimental Procedure for Chemoselective
Reduction of a-Keto Amides using K3PO4 Catalyst
1
s:ethyl acetate, 70:30 v/v); H NMR (400 MHz, DMSO-d6):
d=9.36 (s, 1H), 7.60 (m, 2H), 7.26–7.41 (m, 3H), 6.99–7.06
(m, 3H), 6.33 (d, J=4.8 Hz, 1H), 5.12 (d, J=4.8 Hz 1H),
2.02 (s, 6H); 13C NMR (100 MHz, DMSO-d6): d=170.9,
141.3, 135.4, 134.7, 127.9, 127.5, 127.4, 126.6, 126.4, 74.0,
17.9; IR (KBr): n=3447, 1684, 1653, 1559, 1507, 1364 cmÀ1.
2-Hydroxy-N-(naphthalen-1-yl)-2-phenylacetamide (2f):
Colourless solid; mp 113–1148C; Rf =0.55 (hexanes:ethyl
acetate, 90:10 v/v); 1H NMR (400 MHz, DMSO-d6): d=
10.06 (bs, 1H), 7.83–7.99 (m, 2H), 7.78 (d, J=8.4 Hz, 1H),
7.62 (t, J=8.4 Hz, 3H), 7.45–7.57 (m, 3H), 7.29–7.45 (m,
3H), 6.57 (d, J=3.6 Hz, 1H), 5.28 (d, J=4.0 Hz, 1H);
13C NMR (100 MHz, DMSO-d6): d=171.1, 143.0, 133.7,
A
mixture of K3PO4 (0.05 mmol) and a-keto amide
(0.5 mmol) in 1.5 mL of distilled 1,4-dioxane was taken in
an oven-dried reaction tube. The reaction mixture was
stirred at room temperature for 10 min. Then PMHS
(1.0 mmol) was added to the reaction mixture. After that,
the reaction tube was closed with a glass stopper and the re-
sulting reaction mixture was stirred vigorously at room tem-
perature. The progress of the reaction was monitored by
TLC. After complete disappearance of substrate, 10 mL of
2N aqueous NaOH solution was added to the reaction and
the resulting mixture was stirred for 10 min. The reaction
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Potassium Phosphate-Catalyzed Chemoselective Reduction of a-Keto Amides
133.0, 128.2, 128.1, 127.9, 127.7, 126.7, 126.1, 126.0, 125.6,
122.2, 121.7, 74.0; IR (KBr): n=3409, 3005, 1659, 1541,
1499, 1436, 1092 cmÀ1; HR-MS: m/z=300.0990 [M+Na]+,
calcd. for C18H15N1O2Na1: 300.1000.
2-Hydroxy-N-{4-[(2-oxo-2-phenylacetamido)methyl]phen-
yl}-2-phenylacetamide (2n): Colourless solid; mp 176–
1778C; Rf =0.38 (hexanes:ethyl acetate, 70:30 v/v); H NMR
1
(400 MHz, DMSO-d6): d=9.91 (s, 1H), 9.38 (t, J=6.0 Hz,
1H), 7.95–7.99 (m, 2H), 7.64–7.75 (m, 3H), 7.54–7.61 (m,
2H), 7.49–7.53 (m, 2H), 7.32–7.38 (m, 2H), 7.24–7.31 (m,
3H), 6.42 (d, J=4.4 Hz, 1H), 5.10 (d, J=4.4 Hz, 1H), 4.40
(d, J=6.0 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): d=
190.3, 171.1, 164.9, 140.8, 137.5, 134.6, 133.6, 132.9, 129.7,
129.0, 128.1, 127.8, 127.6, 126.6, 119.8, 74.0, 41.5; IR (KBr):
n=3567, 3537, 3058, 1793, 1711, 1612, 1090, 1074 cmÀ1; HR-
MS: m/z=411.1313 [M+Na]+, calcd. for C23H20N2O4Na1:
411.1321.
2-Hydroxy-2-phenyl-N-[4-(trifluoromethyl)phenyl]aceta-
mide (2g): Colourless solid; mp 175–1768C; Rf =0.40 (hexa-
nes:ethyl acetate, 80:20 v/v); 1H NMR (400 MHz, DMSO-
d6): d=10.31 (bs,1H), 7.94 (d, J=8.4 Hz, 2H), 7.65 (d, J=
8.4 Hz, 2H), 7.52 (d, J=7.2 Hz, 2H), 7.26–7.41 (m, 3H),
6.53 (d, J=4.4 Hz, 1H), 5.14 (d, J=4.0 Hz, 1H); 13C NMR
(100 MHz, DMSO-d6): d=171.8, 142.1, 140.5, 134.4, 128.1,
127.9, 127.7, 126.6, 125.9 (q, J=4.0 Hz, CF3), 119.7, 74.1; IR
(KBr): n=3293, 1657, 1601, 1557, 1543, 1116 cmÀ1; HR-MS:
m/z=318.0705 [M+Na]+, calcd. for C15H12N1O2F3Na1:
318.0718.
2-Hydroxy-N-[4-(2-hydroxy-2-phenylacetamido)benzyl]-2-
phenylacetamide (2o): Colourless solid; mp 191–1928C; Rf =
1
2-Hydroxy-N-(3-nitrophenyl)-2-phenylacetamide
(2h):
0.32 (hexanes:ethyl acetate, 60:40 v/v); H NMR (400 MHz,
Colourless solid; mp 142–1438C; Rf =0.42 (hexanes:ethyl
acetate, 70:30 v/v); 1H NMR (400 MHz, DMSO-d6): d=
10.49 (bs,1H), 8.76 (s, 1H), 8.12 (d, J=7.6 Hz, 1H), 7.91
(dd, J=8.2, 1.4 Hz, 1H), 7.48–7.63 (m, 3H), 7.20–7.40 (m,
3H), 6.58 (d, J=4.4 Hz, 1H), 5.16 (d, J=4.0 Hz, 1H);
13C NMR (100 MHz, DMSO-d6): d=172.1, 147.9, 140.5,
139.8, 130.0, 128.2, 127.8, 126.6, 125.9, 118.1, 113.9, 74.1; IR
(KBr): n=3292, 1653, 1647, 1595, 1507, 1062 cmÀ1; HR-MS:
m/z=273.0887 [M+H]+, calcd. for C14H13N2O4: 273.0875.
DMSO-d6): d=9.86 (s, 1H), 8.46 (t, J=6.2 Hz, 1H), 7.58
(dd, J=7.0, 2.0 Hz, 2H), 7.53–7.47 (m, 2H), 7.39–7.44 (m,
2H), 7.23–7.38 (m, 6H), 7.11 (d, J=8.8 Hz, 2H), 6.41 (d, J=
4.8 Hz, 1H), 6.17 (d, J=4.8 Hz, 1H), 5.08 (d, J=4.8 Hz,
1H), 4.95 (d, J=4.8 Hz, 1H), 4.21 (dd, J=6.0, 2.8 Hz, 1H);
13C NMR (100 MHz, DMSO-d6): d=172.2, 171.0, 141.3,
140.9, 137.1, 134.7, 128.1, 127.9, 127.6, 127.4, 126.6, 126.5,
119.6, 74.0, 73.6, 41.3; IR (KBr): n=3552, 3546, 1706, 1700,
1653, 1647, 1636, 1363, 1228 cmÀ1; HR-MS: m/z=411.1470
[M+Na]+, calcd. for C23H22N2O4Na1: 413.1477.
N-(4-Chlorophenyl)-2-hydroxy-2-phenylacetamide
(2i):
Colourless solid; mp 97–988C; Rf =0.36 (hexanes:ethyl ace-
tate, 80:20 v/v); H NMR (400 MHz, DMSO-d6): d=9.64 (s,
2-Hydroxy-2-phenyl-N-(pyridin-2-yl)acetamide (2p): Col-
ourless solid; mp 119–1208C; Rf =0.38 (hexanes:ethyl ace-
tate, 80:20 v/v); H NMR (400 MHz, DMSO-d6): d=9.95 (s,
1
1
1H), 8.09 (dd, J=8.2, 1.4 Hz, 1H), 7.46–7.55 (m, 3H), 7.29–
7.40 (m, 4H), 7.12–7.19 (m, 1H), 6.93 (d, J=4.4 Hz, 1H),
5.18 (d, J=4.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6):
d=170.8, 140.4, 134.1, 129.3, 128.2, 127.83, 127.8, 126.7,
125.5, 123.8, 122.2, 73.6; IR (KBr): n=3235, 1666, 1614,
1604, 1556, 1072 cmÀ1.
1H), 8.30–8.35 (m, 1H), 8.03 (dt, J=8.4, 0.8 Hz, 1H), 7.75–
7.82 (m, 1H), 7.48–7.54 (m, 2H), 7.25–7.39 (m, 3H), 7.09–
7.16 (m, 1H), 6.52 (d, J=5.2 Hz, 1H), 5.23 (d, J=5.2 Hz,
1H); 13C NMR (100 MHz, DMSO-d6): d=171.4, 151.0,
148.1, 140.4, 138.4, 128.1, 127.7, 126.6, 119.9, 113.1, 73.3; IR
N-(4-Chlorophenyl)-2-hydroxy-2-phenylacetamide (2j):[27]
Colourless solid; mp 159–1608C (Lit.[27] mp 161–1648C);
Rf =0.54 (hexanes:ethyl acetate, 80:20 v/v); 1H NMR
(400 MHz, DMSO-d6): d=10.08 (s, 1H), 7.75 (dd, J=6.8,
2.0 Hz, 2H), 7.51 (d, J=7.2 Hz, 2H), 7.39–7.26 (m, 5H),
6.48 (d, J=4.8 Hz, 1H), 5.10 (d, J=4.8 Hz, 1H); 13C NMR
(100 MHz, DMSO-d6): d=171.4, 140.7, 137.5, 128.5, 128.1,
127.7, 127.1, 126.6, 121.3, 74.0; IR (KBr): n=3298, 1696,
1684, 1653, 1522, 1065 cmÀ1; HR-MS: m/z=284.0460 [M+
Na]+, calcd. for C14H12N1O2Cl1Na1: 284.0454.
(KBr): n=3358, 1671, 1577, 1517, 1507, 1436, 1304 cmÀ1
;
HR-MS:
m/z=251.0791
[M+Na]+,
calcd.
for
C13H12N2O2Na1: 251.0796.
2-Hydroxy-N-methyl-N,2-diphenylacetamide (2q):[14] Col-
ourless solid; mp 89–908C (Lit.[14] mp 89–908C); Rf =0.40
(hexanes:ethyl acetate, 80:20 v/v); 1H NMR (400 MHz,
CDCl3): d=7.08–7.35 (m, 6H), 6.70–6.90 (m, 4H), 5.00 (s,
1H), 3.30 (s, 1H); 13C NMR (100 MHz, CDCl3): d=173.0,
141.6, 139.4, 129.7, 128.5, 128.2, 128.1, 127.4, 71.8, 38.4; IR
(KBr): n=3422, 1648, 1605, 1594, 1496, 1369, 1085 cmÀ1.
N-(4-Cyanophenyl)-2-hydroxy-2-phenylacetamide (2k):[14]
Colourless solid; mp 131–1328C (Lit.[14] mp 130–1318C);
Rf =0.38 (hexanes:ethyl acetate, 80:20 v/v); 1H NMR
(400 MHz, DMSO-d6): d=10.36 (s, 1H), 7.93 (d, J=8.8 Hz,
2H), 7.75 (d, J=8.8 Hz, 2H), 7.51 (d, J=7.2 Hz, 2H), 7.26–
7.41 (m, 3H), 6.55 (d, J=4.4 Hz, 1H), 5.15 (d, J=4.4 Hz,
1H); 13C NMR (100 MHz, DMSO-d6): d=172.1, 142.8,
140.4, 133.1, 128.2, 127.8, 126.6, 119.8, 118.99, 105.3, 74.1; IR
(KBr): n=3670, 1946, 1675, 1653, 1603, 1559 cmÀ1.
4-(2-Hydroxy-2-phenylacetamido)benzamide (2l): Colour-
less solid; mp 161–1628C; Rf =0.32 (hexanes:ethyl acetate,
70:30 v/v); 1H NMR (400 MHz, DMSO-d6): d=10.12 (s,
1H), 7.70–7.95 (m, 5H), 7.52 (d, J=6.8 Hz, 2H), 7.16–7.44
(m, 4H), 6.48 (s, 1H), 5.13 (s, 1H); 13C NMR (100 MHz,
DMSO-d6): d=171.5, 167.3, 141.1, 140.6, 129.1, 128.2, 128.1,
127.7, 126.6, 118.8, 70.0; IR (KBr: n=3361, 1653, 1623,
1596, 1522 cmÀ1.
N-Ethyl-2-hydroxy-N,2-diphenylacetamide
(2r):
Oily
1
liquid; Rf =0.44 (hexanes:ethyl acetate, 80:20 v/v); H NMR
(400 MHz, CDCl3): d=7.10–7.34 (m, 6H), 6.69–6.85 (m,
4H), 4.92 (s, 1H), 3.87–4.00 (m, 1H), 3.52–3.64 (m, 1H) 3.35
(bs, 1H), 1.12 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=172.4, 139.9, 139.6, 129.5, 129.2, 128.5, 128.4,
128.1, 127.5, 71.9, 45.5, 12.9; IR (neat): n=3421, 3063, 1652,
1595, 1454, 1380, 1092 cmÀ1.
2-Hydroxy-N-(4-methoxybenzyl)-2-phenylacetamide (2s):
Colourless solid; mp 141–1428C; Rf 0.36 (hexanes:ethyl ace-
1
tate, 80:20 v/v); H NMR (400 MHz, CDCl3): d=7.32–7.45
(m, 5H), 7.11 (d, J=7.6 Hz, 2H), 6.83 (d, J=7.6 Hz, 2H),
6.43 (bs, 1H), 5.06 (s, 1H), 4.37 (d, J=6.8 Hz, 2H), 3.78 (s,
3H), 2.38 (bs, 1H); 13C NMR (100 MHz, CDCl3): d=172.1,
159.2, 139.5, 129.9, 129.2, 129.1, 128.9, 127.0, 114.2, 74.4,
55.4, 43.3; IR (KBr): n=3220, 2965, 1712, 1635, 1540, 1459,
1065 cmÀ1.
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Alagesan Muthukumar et al.
N-(2-Chlorobenzyl)-2-hydroxy-2-phenylacetamide
(2t):
Experimental Procedure for O-Arylation of a-
Colourless solid; mp 124–1258C; Rf =0.43 (hexanes:ethyl
acetate, 80:20 v/v); 1H NMR (400 MHz, CDCl3): d=7.31–
7.40 (m, 6H), 7.15–7.25 (m, 3H), 6.80 (bs, 1H), 5.02 (s, 1H),
4.49 (d, J=6.0 Hz, 2H), 2.96 (bs, 1H); 13C NMR (100 MHz,
CDCl3): d=172.4, 139.4, 135.2, 133.7, 130.0, 129.7, 129.2,
129.0, 128.8, 127.2, 126.9, 74.3, 41.6; IR (KBr): n=3230,
3058, 1682, 1605, 1510, 1468, 1050 cmÀ1.
Hydroxy Amides
To an oven-dried reaction tube, a-hydroxy amide
(0.5 mmol), phenyl iodide (0.6 mmol), CuI (0.025 mmol),
1,2-bipyridine (0.05 mmol), and Cs2CO3 (1.0 mmol) were
added and the reaction tube was evacuated and refilled with
nitrogen. Then dry DMF (1.5 mL) was added and the reac-
tion mixture was stirred at 1008C under a nitrogen atmos-
phere for 24 h. The completion of reaction was monitored
by TLC. After the completion of reaction, the reaction mix-
ture was extracted three times with ethylacetate water mix-
ture and the combined organic layer was dried over MgSO4
and evaporated under reduced pressure. The solid residue
was purified by silica gel column chromatography.
2-Phenoxy-N,2-diphenylacetamide (8): Colourless solid;
mp 124–1258C; Rf =0.58 (hexanes:ethyl acetate, 80:20 v/v);
1H NMR (400 MHz, CDCl3): d=8.44 (bs, 1H), 7.54–7.63 (m,
4H), 7.27–7.43 (m, 7H), 7.09–7.16 (m, 1H), 7.00–7.06 (m,
3H), 5.65 (s, 1H); 13C NMR (100 MHz, CDCl3): d=167.9,
156.8, 137.2, 136.3, 130.0, 129.2, 128.9, 128.8, 126.7, 124.9,
122.8, 120.2, 116.2, 80.9; IR (KBr): n=3284, 1685, 1676,
1599, 1055 cmÀ1.
N-(3-Acetylphenyl)-2-hydroxy-2-phenylacetamide (6a):[14]
Pale yellow solid; mp 116–1178C (Lit.[14] mp 118–1198C);
Rf =0.38 (hexanes:ethyl acetate, 70:30 v/v); 1H NMR
(400 MHz, DMSO-d6): d=10.14 (s, 1H), 8.32 (t, J=1.8 Hz,
1H), 7.94–8.01 (m, 1H), 7.62–7.68 (m, 1H), 7.50–7.56 (m,
2H), 7.44 (t, J=8.0 Hz, 1H), 7.33–7.40 (m, 2H), 7.26–7.32
(m, 1H), 6.47 (d, J=4.8 Hz, 1H), 5.13 (d, J=4.4 Hz, 1H),
2.54 (s, 3H); 13C NMR (100 MHz, DMSO-d6): d=197.7,
171.6, 140.7, 138.9, 137.3, 129.0, 128.1, 127.7, 126.6, 124.2,
123.4, 119.2, 74.1, 26.7; IR (KBr): n=3308, 1653, 1591, 1559,
1540, 1490, 1062 cmÀ1.
N-(4-Acetylphenyl)-2-hydroxy-2-phenylacetamide (6b):[14]
Colourless solid; mp 149–1508C (Lit.[14] mp 148–1498C);
Rf =0.39 (hexanes:ethyl acetate, 70:30 v/v); 1H NMR
(400 MHz, DMSO-d6): d=10.77 (s, 1H), 8.34–8.48 (m, 4H),
8.04 (d, J=8.0 Hz, 2H), 7.87 (t, J=7.4 Hz, 2H), 7.78–7.84
(m, 1H), 7.02 (d, J=4.4 Hz, 1H), 5.66 (d, J=4.4 Hz, 1H),
3.03 (s, 3H); 13C NMR (100 MHz, DMSO-d6): d=196.6,
171.8, 142.9, 140.5, 132.0, 129.3, 128.2, 127.7, 126.6, 119.0,
74.1, 26.4; IR(KBr): n=3285, 1674, 1657, 1598, 1543,
1183 cmÀ1.
Experimental Procedure for O-Silylation of a-
Hydroxy Amides
Triphenylsilyl chloride (0.6 mmol) was added dropwise to
a stirred mixture of a-hydroxy amide (0.5 mmol) and Et3N
(1 mmol) in dry CH2Cl2 (1.5 mL) at 08C under a nitrogen
atmosphere. The stirring was continued for 12 h in room
temperature and the completion of reaction was monitored
by TLC. The organic layer was washed with water for two
N-(3-Benzoylphenyl)-2-hydroxy-2-phenylacetamide
(6c):[14] Colourless solid; mp 124–1258C (Lit.[14] mp 126–
1278C); Rf =0.35 (hexanes:ethyl acetate, 70:30 v/v);
1H NMR(400 MHz, CDCl3): d=8.52 (s, 1H), 7.89–7.96 (m,
1H), 7.74–7.85 (m, 3H), 7.58 (tt, J=7.4, 1,2 Hz, 1H), 7.43–
7.51 (m, 5H), 7.32–7.43 (m, 4H), 5.17 (d, J=3.6 Hz, 1H),
3.76 (d, J=3.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
196.5, 170.5, 138.9, 138.5, 137.5, 137.3, 132.9, 130.2, 129.2,
129.1, 129.0, 128.5, 126.9, 126.4, 123.9, 121.1, 74.8; IR (KBr):
n=3335, 3307, 1696, 1654, 1542, 1106, 1028 cmÀ1.
times then
a saturated aqueous solution of NaHCO3
(10 mL) was slowly added to the reaction mixture. The or-
ganic layer was dried over MgSO4 and evaporated under re-
duced pressure. The solid residue was purified by silica gel
column chromatography.
N,2-Diphenyl-2-[(triphenylsilyl)oxy]acetamide (9): Col-
ourless semi-solid; Rf =0.60 (hexanes:ethyl acetate, 80:20
1
v/v); H NMR (400 MHz, CDCl3): d=8.76 (bs, 1H), 7.62–
Experimental Procedure for O-Acylation of a-
Hydroxy Amides
7.67 (m, 2H), 7.54–7.60 (m, 6H), 7.44–7.50 (m, 3H), 7.34–
7.43 (m, 9H), 7.24–7.32 (m, 4H), 7.06–7.13 (m, 1H), 5.36 (s,
1H); 13C NMR (100 MHz, CDCl3): d=169.6, 138.9, 137.3,
135.6, 135.5, 135.4, 135.1, 132.8, 130.8, 130.3, 129.1, 128.6,
128.44, 128.41, 128.38, 128.34, 128.30, 128.28, 128.1, 126.8,
124.6, 119.7; IR (neat): n=3393, 1653, 1647, 1601, 1091,
1067 cmÀ1.
Acetyl chloride (0.6 mmol) was added dropwise to a stirred
mixture of a-hydroxy amide (0.5 mmol) and Et3N (1 mmol)
in dry CH2Cl2 (1.5 mL) at 08C under a nitrogen atmosphere.
The stirring was continued for 12 h at room temperature
and the completion of reaction was monitored by TLC. The
organic layer was washed with water for two times, then a sa-
turated aqueous solution of NaHCO3 (10 mL) was slowly
added to the reaction mixture. The organic layer was sepa-
rated, washed with water (3”10 mL), dried over MgSO4 and
evaporated under reduced pressure. The solid residue was
purified by silica gel column chromatography.
Experimental Procedure for O-Methylation of a-
Hydroxy Amides
Methyl iodide (1.0 mmol) was added dropwise to a stirred
mixture of a-hydroxy amide (0.5 mmol) and K2CO3
(1.0 mmol) in dry THF (1.5 mL) at room temperature under
a nitrogen atmosphere. The stirring was continued for 12 h
and the completion of reaction was monitored by TLC.
After the completion of reaction, the reaction mixture was
extracted three times with an ethyl acetate/water mixture
and the combined organic layer was dried over MgSO4 and
evaporated under reduced pressure. The residue was puri-
fied by silica gel column chromatography.
2-Oxo-1-phenyl-2-(phenylamino)ethyl acetate (7): Colour-
less solid; mp 118–1198C; Rf =0.52 (hexanes:ethyl acetate,
1
80:20 v/v); H NMR (400 MHz, CDCl3): d=7.86 (bs, 1H),
7.46–7.56 (m, 4H), 7.35–7.43 (m, 3H), 7.31 (t, J=8.0 Hz,
2H), 7.13 (t, J=7.4 Hz, 1H), 6.20 (s, 1H), 2.24 (s, 3H);
13C NMR (100 MHz, CDCl3): d=169.3, 166.5, 137.0, 135.3,
129.4, 129.2, 129.1, 127.6, 125.1, 120.2, 75.9, 21.2; IR (KBr):
n=3327, 1749, 1685, 1681, 1432, 1031 cmÀ1.
650
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FULL PAPERS
Potassium Phosphate-Catalyzed Chemoselective Reduction of a-Keto Amides
2-Methoxy-N,2-diphenylacetamide (10): Colourless solid;
mp 102–1038C; Rf =0.56 (hexanes:ethyl acetate, 80:20 v/v);
1H NMR (400 MHz, CDCl3): d=8.56 (bs, 1H), 7.56–7.63 (m,
2H), 7.44–7.49 (m, 2H), 7.29–7.42 (m, 5H), 7.08–7.15 (m,
1H), 4.74 (s, 1H), 3.46 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=168.6, 137.4,136.7, 129.1, 128.8, 128.7, 127.2,
124.5, 119.8, 84.0, 57.5; IR (KBr): n=3232, 1666, 1660, 1651,
1600, 1066 cmÀ1.
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1-Methyl-3-phenylindolin-2-one (11r): Colourless solid;
mp 118–1198C; Rf =0.35 (hexanes:ethyl acetate, 80:20 v/v);
1H NMR (400 MHz, CDCl3): d=7.27–7.37 (m, 4H), 7.15–
7.23 (m, 3H), 7.07 (td, J=7.5, 0.8 Hz, 1H); 6.90 (d, J=
7.6 Hz, 1H), 4.61 (s, 1H), 3.26 (s, 3H); 13C NMR (100 MHz,
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96–978C; Rf =0.38 (hexanes:ethyl acetate, 80:20 v/v);
1H NMR (400 MHz, CDCl3): d=7.27–7.36 (m, 4H), 7.14–
7.22 (m, 3H), 7.05 (td, J=7.4, 0.8 Hz, 1H); 6.92 (d, J=
8.0 Hz, 1H), 4.59 (s, 1H), 3.81 (q, J=7.2 Hz, 2H), 1.30 (t,
J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=175.8,
143.7, 137.0, 129.4, 129.0, 128.5, 128.4, 128.6, 125.4, 122.6,
108.4, 52.2, 35.0, 12.8; IR (KBr): n=1711, 1612, 1489, 1353,
1225, 1090 cmÀ1.
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Acknowledgements
We thank DST (project No.: SB/S1/OC-72/2013) for financial
support. ALM and MNC thank CSIR, New Delhi for senior
research fellowships.
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