Microwave-assisted conversion of N-substituted oxazolidin-2,4-diones into α-hydroxyamides

Article abstract of DOI:10.1016/j.tet.2005.05.029

N-Substituted oxazolidin-2,4-diones have been synthesized in a novel one-pot reaction by reacting cyanohydrins stepwise with 1,1′- carbonyldiimidazole and primary amines followed by acidic hydrolysis of the intermediate 4-imino-oxazolidin-2-ones. Their mi

Full text of DOI:10.1016/j.tet.2005.05.029

Tetrahedron 61 (2005) 7247–7251
Microwave-assisted conversion of N-substituted
oxazolidin-2,4-diones into a-hydroxyamides
*
Thomas Kurz and Khalid Widyan
Institute of Pharmacy, University of Hamburg, Bundesstrasse 45, 20146 Hamburg, Germany
Received 18 March 2005; revised 9 May 2005; accepted 11 May 2005
Available online 13 June 2005
Abstract—N-Substituted oxazolidin-2,4-diones have been synthesized in a novel one-pot reaction by reacting cyanohydrins stepwise with
1,10-carbonyldiimidazole and primary amines followed by acidic hydrolysis of the intermediate 4-imino-oxazolidin-2-ones. Their
microwave-assisted conversion into a-hydroxyamides was accomplished by treatment with catalytic amounts of sodium methoxide in
methanol.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2,3-epoxyamides with samarium diiodide.18 Katritzky
reported the synthesis of a-hydroxyamides by treatment of
mandelic acid with N-(1-methanesulfonyl)benzotriazole
and primary amines.19
The a-hydroxyamide moiety is a well known pharmaco-
phore that is present in various biologically active
compounds. a-Hydroxyamides have, for example, been
identified as inhibitors of methionine aminopeptidase-2 and
as HIV protease inhibitors.1,2 Mycalamides are a class of
a-hydroxyamides which exhibit potent antitumour activity.3
a-Hydroxyamides are as well valuable intermediates in the
synthesis of natural products and various biologically active
compounds.4–6 Known methods for their preparation can be
divided into four main categories: reactions of carboxylic
acids and activated acid derivatives with amines, reduction
of a-ketoamides, micellaneous methods and the synthesis of
a-hydroxyamides via cyclic precursors.
1,3-Dioxolane-2,4-diones, acetonides of a-hydroxy-
carboxylic acids and oxazolidin-2,4-diones have been used
as cyclic precursors in the preparation of a-hydroxy-
amides.20–22 Commonly the alkaline hydrolysis of oxazo-
lidin-2,4-diones leads to a mixture of a-carbamoyloxyacid
and a-hydroxyamide.22 Tamariz described the synthesis of
two a-hydroxycarboxamides in 34 and 35% yield by
alkaline hydrolysis of the corresponding oxazolidin-2,4-
diones.23 Furthermore, Miethchen reported the conversion
of a 5,5-disubstituted 3-cyclohexyloxazolidin-2,4-dione
into the corresponding a-hydroxy N-cyclohexylcarboxa-
mide by refluxing the oxazolidin-2,4-dione in methanol in
the presence of an excess of sodium methoxide for 7 h in
97% yield.24
The conversion of a-hydroxyacids into a-hydroxyamides
has been accomplished in moderate to high yields at high
temperature, high pressure, Lewis acid catalyzed, by
treatment of a-hydroxyacids with N-sulfinylanilines and
by aminolysis of O-TMS-protected acid chlorides.7–12
Reactions of a-hydroxyesters with amines usually require
long reaction times, forcing or enzyme catalyzed reaction
conditions.13 The reduction of a-ketoamides has for
instance been accomplished with sodium borohydride,
LiBEt3H, KBEt3H, with magnesium- and titanium-based
reagents and by catalytic hydrogenation in the presence of
palladium on charcoal.14–17 A novel method for the
synthesis of a-hydroxyamides represents the reaction of
Given the importance of the a-hydroxyamide functionality
in organic and medicinal chemistry, development of new
methods for the efficient synthesis of a-hydroxyamides is
still an important challenge. Our group reported the sodium
methoxide catalyzed decarbonylation of O-substituted
3-hydroxyoxazolidin-2,4-diones, N-substituted 3-amino-
oxazolidin-2,4-diones and O-substituted 3-hydroxy-4-
imino oxazolidin-2-ones as novel methods for the synthesis
of O-substituted a-hydroxyhydroxamic acids, N0,N0-
disubstituted a-hydroxyhydrazides and O-substituted
a-hydroxyamidoximes.25 We now report the microwave-
assisted conversion of N-substituted oxazolidin-2,4-diones
into a-hydroxyamides. A comparison of the microwave-
Keywords: Amides; Microwave chemistry; Oxazolidin-2,4-diones; Ring
opening.
Corresponding author. Tel./fax: C49 40 42838 3467;
e-mail: kurz@chemie.uni-hamburg.de
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.05.029

7248
T. Kurz, K. Widyan / Tetrahedron 61 (2005) 7247–7251
chemistry to the conventional and sealed tube decarbonyl-
ation is exemplarily described.
2. Results and discussion
2.1. Synthesis of N-substituted oxazolidin-2,4-diones
(5a–i)
N-Substituted oxazolidin-2,4-diones (5) have been prepared
in a novel one pot reaction starting from cyanohydrins (1),
1,10-carbonyldiimidazole (CDI) and primary amines. Reac-
tions of 1 with CDI in dichloromethane furnished
imidazolide intermediates 2. Their treatment with primary
amines gave the open-chained carbamate intermediates 3.
Base catalyzed ring closure of 3 furnished 4-imino
oxazolidin-2-ones (4), which were subsequently hydrolyzed
to afford 5 in 53–75% yield (Scheme 1, Table 1).
Scheme 1. Synthesis of oxazolidin-2,4-diones (5a–i).
Table 1. Synthesis of oxazolidin-2,4-diones (5a–i)
Due to the characteristic C]O absorption bands of 2–5 the
progression of the reaction was readily monitored by IR
spectroscopy. N-Substituted oxazolidin-2,4-diones (5),
which have attracted much attention in medicinal and
agricultural chemistry,26 have, for example, previously been
prepared from a-hydroxyesters and isocyanates and by
reactions of a-hydroxyamides with chloroformates or
dialkyl carbonates.22,26
5
R1
R2
Yield (%)
a
b
c
d
e
f
g
h
i
C6H5
m-FC6H4
m-FC6H4
70
70
75
55
53
68
65
67
63
1-Naphthyl
Cyclopropyl
2-Thienyl
2-Furyl
p-NCC6H4
p-F3CC6H4
p-BrC6H4
p-ClC6H4
Cyclopropyl
p-FC6H4CH2
CH3
2.2. Synthesis of a-hydroxyamides (6a–i)
C6H11
Microwave-assisted synthesis of 6a–f was accomplished in
high yields of 80–92% by reacting 5a–f with sodium
methoxide (0.2 equiv) in methanol for 3.5–4.5 min
(Scheme 2, Table 2). The corresponding reaction of
compound 5a in a sealed tube at 105 8C afforded compound
6a in 78% yield after 12 min, while conventional heating at
atmospheric pressure provided 6a in 89% yield after 45 min.
1-Naphthyl
p-MeC6H4
p-MeC6H4
Microwave-assisted synthesis of N-cyclopropyl, N-(4-
fluorobenzyl) and N-methyl substituted a-hydroxyamides
6g–i was achieved in moderate to good yields of 55–82%
using longer reaction times and harsher reaction conditions.
In contrast to the fast microwave-assisted conversion of 5h
into 6h, the corresponding reaction in a sealed tube at
105 8C took 9 h to give 6h in only 31% yield. Refluxing 5h
for 35 h in methanol in the presence of sodium methoxide
(0.2 equiv) afforded 39% of 6h (Table 2).
Scheme 2. Synthesis of a-hydroxyamides (6a–i).
Table 2. Synthesis of a-hydroxyamides (6a–i)
6
R1
R2
Hold time
microwave
(min)
Yield (%)
Time
conventional
Yield (%)
Time
sealed tube
Yield (%)
a
b
c
d
e
f
g
h
i
C6H5
m-FC6H4
m-FC6H4
p-NCC6H4
p-F3CC6H4
p-BrC6H4
p-ClC6H4
Cyclopropyl
p-FC6H4CH2
CH3
4.5
4.5
4.5
3.5
4
4.5
14.5
20
90
91
87
80
92
84
82
73
55
45 min
—
—
—
—
—
—
35 h
—
89
—
—
—
—
—
—
39
—
12 min
—
—
—
—
—
—
9 h
—
78
—
—
—
—
—
—
31
—
1-Naphthyl
Cyclopropyl
2-Thienyl
2-Furyl
C6H11
1-Naphthyl
p-MeC6H4
p-MeC6H4
90
Microwave reactions were conducted at 100 8C (6a–g) or 150 8C (6h,i) in the presence of 0.2 equiv of sodium methoxide in methanol using microwave glass
pressure tubes.

T. Kurz, K. Widyan / Tetrahedron 61 (2005) 7247–7251
7249
3. Conclusion
4.1.1. 3-(3-Fluorophenyl)-5-phenyloxazolidin-2,4-dione
(5a). Colorless solid (70%). Mp 140 8C (EtOAc–hexane);
IR (KBr) nZ1820, 1734 cmK1; 1H NMR (CDCl3) d (ppm):
5.91 (s, 1H), 7.12–7.17 (m, 1H), 7.25–7.33 (m, 2H), 7.44–
7.61 (m, 6H); 13C NMR (CDCl3) d (ppm): 80.3, 113.4,
116.4, 116.6, 121.3, 121.4, 126.4, 129.7, 130.4, 130.9,
131.1, 131.6, 161.8, 164.3. Anal. Calcd for C15H10FNO3:
C, 66.42; H, 3.72; N, 5.16. Found: C, 66.28; H, 3.70; N,
5.18.
We have developed a convenient two-step synthesis for the
preparation of a-hydroxyamides using conventional and
microwave-assisted chemistry. The first step is a novel one
pot-synthesis of N-substituted oxazolidin-2,4-diones. In the
second step we have demonstrated that N-substituted
3-amino-oxazolidin-2,4-diones are valuable precursors for
the microwave-assisted synthesis of a-hydroxyamides in
moderate to high yields. In comparison to conventional
heating at atmospheric pressure and reactions under
pressure, the microwave-assisted conversion of N-substi-
tuted oxazolidin-2,4-diones into a-hydroxyamides proceeds
faster and in higher yields. Compared to Shapiro’s and
Tamariz’s methods, the yields of our method are higher, no
a-carbamoyloxyacids have been detected and the use of
water as a solvent has been avoided. Starting from
cyanohydrins our method allows the introduction of
different substituents in the a-position of the title com-
pounds. The method is practical and only catalytic amounts
of sodium methoxide are necessary for the decarbonylation.
The oxazolidin-2,4-dione ring system represents a protect-
ing group for the secondary alcoholic hydroxyl group and
the amide nitrogen.
4.1.2. 3-(3-Fluorophenyl)-5-(1-naphthyl)oxazolidin-2,4-
dione (5b). Colorless solid (70%). Mp 204 8C (THF–
Et2O); IR (KBr) nZ1811, 1734 cmK1; 1H NMR (CDCl3) d
(ppm): 6.69 (s, 1H), 7.16 (t, JZ7.12 Hz, 1H), 7.31–7.38 (m,
2H), 7.46–7.68 (m, 5H), 7.96 (t, JZ8.90 Hz, 2H), 8.10 (d,
JZ7.89 Hz, 1H); 13C NMR (CDCl3) d (ppm): 78.6, 113.4,
113.7, 116.4, 116.6, 121.4, 123.5, 124.7, 125.6, 127.1,
127.9, 129.5, 130.9, 131.1, 131.5, 153.5, 167.9. Anal. Calcd
for C19H12FNO3: C, 71.03; H, 3.76; N, 4.36. Found: C,
70.93; H, 3.75; N, 4.43.
4.1.3. 3-(4-Cyanophenyl)-5-cyclopropyloxazolidin-2,4-
dione (5c). Colorless solid (75%). Mp 163 8C (THF–
Et2O); IR (KBr) nZ2222, 1805, 1745 cmK1 1H NMR
;
(CDCl3) d (ppm): 0.64–0.89 (m, 4H), 1.32–1.40 (m, 1H),
4.61 (d, JZ7.12 Hz, 1H), 7.70 (d, JZ8.65 Hz, 2H), 7.80 (d,
JZ8.65 Hz, 2H); 13C NMR (CDCl3) d (ppm): 0.3, 9.7, 79.9,
110.5, 115.9, 123.6, 131.2, 132.9, 150.9, 171.5. Anal. Calcd
for C13H10N2O3: C, 64.46; H, 4.16; N, 11.56. Found: C,
64.19; H, 4.20; N, 11.55.
4. Experimental
Cyanohydrins (1) have been prepared according to an
established literature procedure and were used immediately
after structure conformation by IR spectroscopy.27 Micro-
wave assisted reactions were carried out using a CEM
microwave reactor model Discover. Melting points
(uncorrected) were determined on a Mettler FP 62
apparatus. Elemental analysis was carried out with a
Heraeus CHN-O-Rapid instrument. IR spectra were
4.1.4. 5-(2-Thienyl)-3-(4-trifluoromethylphenyl)oxazoli-
din-2,4-dione (5d). Colorless solid (55%). Mp 190 8C
1
(Et2O–hexane); IR (KBr) nZ1807, 1732 cmK1; H NMR
(CDCl3) d (ppm): 6.10 (s, 1H), 7.10 (m, 1H), 7.32 (d, JZ
3.56 Hz, 1H), 7.50 (d, JZ6.36 Hz, 1H), 7.68 (d, JZ
8.65 Hz, 2H), 7.79 (d, JZ8.65 Hz, 2H); 13C NMR (CDCl3)
d (ppm): 77.1, 126.0, 126.9, 127.0, 127.1, 128.0, 128.6,
128.8, 132.7, 153.0, 168.9. Anal. Calcd for C14H8F3NO3S:
C, 51.38; H, 2.46; N, 4.28; S, 9.80. Found: C, 51.21; H, 2.59;
N, 4.20; S, 10.00.
1
recorded on a Shimadzu FT-IR 8300. H NMR (400 MHz)
and 13C NMR (100 MHz) spectra were recorded on a Bruker
AMX 400 spectrometer using tetramethylsilane as an
internal standard and CDCl3 as solvent.
4.1. General procedure for the preparation of
substituted 3-amino-oxazolidin-2,4-diones (5a–i)
4.1.5. 3-(4-Bromophenyl)-5-(2-furyl)oxazolidin-2,4-
dione (5e). Brown solid (53%) after column chromato-
graphy EtOAc–hexane. Mp 144 8C; IR (KBr) nZ1825,
A solution of cyanohydrin 1 (5 mmol) in dry CH2Cl2 (5 mL)
was added dropwise over a period of 10 min to a suspension
of 1,10-carbonyldiimidazole (851 mg, 5.25 mmol) in dry
CH2Cl2 (5 mL) under ice cooling. After stirring at room
temperature for 10 min a solution of the appropriate amine
(5 mmol) in dry CH2Cl2 (5 mL) was added and the reaction
mixture was stirred at room temperature for 1 h. Triethyl-
amine (3 mL) was added and the reaction mixture was
stirred until two sharp bands in the IR spectra appeared at
1780–1800 and 1680–1700 cmK1. The solvent was
removed under reduced pressure and the residue was
dissolved in THF (10 mL). Hydrochloric acid (10 mL,
20%) was added under ice cooling and the reaction mixture
was stirred for 50 min. The reaction mixture was extracted
thrice with EtOAc (15 mL) and the combined extracts were
dried over MgSO4. Removal of the solvent afforded 5a–i as
solids, analytically pure products were obtained after
recrystallization from the indicated solvent or purification
by column chromatography.
1
1744 cmK1; H NMR (CDCl3) d (ppm): 5.91 (s, 1H), 6.47
(dd, JZ3.31, 1.78 Hz, 1H), 6.70 (d, JZ3.65 Hz, 1H), 7.40
(d, JZ8.90 Hz, 2H), 7.53 (m, 1H), 7.65 (d, JZ8.90 Hz,
2H); 13C NMR (CDCl3) d (ppm): 74.5, 111.5, 114.4, 123.4,
127.5, 130.2, 133.1, 143.9, 145.7, 153.4, 167.9. Anal. Calcd
for C13H8BrNO4: C, 48.47; H, 2.50; N, 4.35. Found: C,
48.28; H, 2.59; N, 4.30.
4.1.6. 3-(4-Chlorophenyl)-5-cyclohexyloxazolidin-2,4-
dione (5f). Colorless solid (68%). Mp 163 8C (THF–
1
Et2O); IR (KBr) nZ1805, 1744 cmK1; H NMR (CDCl3)
d (ppm): 1.14–1.40 (m, 5H), 1.64–1.90 (m, 5H), 2.04–2.14
(m, 1H), 4.77 (d, JZ3.81 Hz, 1H), 7.38 (d, JZ8.90 Hz,
2H), 7.46 (d, JZ8.90 Hz, 2H); 13C NMR (CDCl3) d (ppm):
25.9, 26.0, 26.1, 26.2, 28.7, 40.3, 83.7, 127.1, 129.7,
130.0, 135.1, 154.4, 171.5. Anal. Calcd for C15H16ClNO3:
C, 61.33; H, 5.49; N, 4.77. Found: C, 61.13; H, 5.59; N,
4.74.

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T. Kurz, K. Widyan / Tetrahedron 61 (2005) 7247–7251
4.1.7. 3-Cyclopropyl-5-(1-naphthyl)oxazolidin-2,4-dione
(5g). Colorless solid (65%). Mp 139 8C (THF–Et2O). IR
solution was concentrated to 0.5 mL. Addition of Et2O and
hexane provided 6a,h as solid compounds.
1
(KBr) nZ1811, 1736 cmK1; H NMR (CDCl3) d (ppm):
1.02–1.11 (m, 4H), 2.77–2.83 (m, 1H), 6.43 (s, 1H), 7.44–
7.50 (m, 2H), 7.54–7.63 (m, 2H), 7.89–7.93 (m, 2H), 8.03
(d, JZ8.65 Hz, 1H); 13C NMR (CDCl3) d (ppm): 5.4, 5.5,
23.5, 77.9, 123.6, 124.4, 125.5, 126.9, 127.6, 127.9, 129.4,
131.1, 131.3, 134.4, 155.6, 171.9. Anal. Calcd for
C16H13NO3: C, 71.90; H, 4.90; N, 5.24. Found: C, 71.81;
H, 5.01; N, 5.26.
Conventional method for the synthesis of 6a,h. Sodium
methoxide (0.1 mmol) was added to a stirred solution of
5a,h (0.5 mmol) in methanol (5 mL). After being refluxed
for the indicated time (Table 2), the solvent was evaporated,
water (0.5 mL) was added and the mixture was extracted
thrice with dichloromethane (15 mL). The combined
extracts were dried over MgSO4 and the solution was
concentrated to 0.5 mL. Addition of Et2O and hexane
provided 6a,h as solid compounds.
4.1.8. 3-(4-Fluorobenzyl)-5-(4-methylphenyl)oxazolidin-
2,4-dione (5h). Colorless solid (67%). Mp 130 8C (THF–
Et2O); IR (KBr) nZ1809, 1736 cmK1; 1H NMR (CDCl3) d
(ppm): 2.36 (s, 3H), 4.68 (s, 2H), 5.68 (s, 1H), 7.02 (t, JZ
8.65 Hz, 2H), 7.19–7.23 (m, 4H), 7.40 (d, JZ8.14 Hz, 2H);
13C NMR (CDCl3) d (ppm): 21.7, 43.7, 80.9, 116.2, 116.4,
126.5, 128.8, 130.3, 130.9, 131.2, 131.3, 140.5, 164.4,
171.5. Anal. Calcd for C17H14FNO3: C, 68.22; H, 4.71; N,
4.68. Found: C, 68.29; H, 4.93; N, 4.80.
4.2.1. N-(3-Fluorophenyl)-2-hydroxy-2-phenylacetamide
(6a). Parameter A. Colorless solid (90%). Mp 163 8C
1
(Et2O–hexane); IR (KBr) nZ3302, 3229, 1660 cmK1; H
NMR (CDCl3) d (ppm): 3.50 (s, 1H), 5.87 (s, 1H), 7.12–7.17
(m, 1H), 7.25–7.33 (m, 2H), 7.44–7.61 (m, 6H), 8.12 (s,
1H); 13C NMR (CDCl3) d (ppm): 80.3, 113.4, 116.4, 116.6,
121.3, 121.4, 126.4, 129.7, 130.3, 130.9, 131.1, 131.7,
170.1. Anal. Calcd for C14H12FNO2: C, 68.56, H, 4.93; N,
5.71. Found: C, 68.43; H, 5.01; N, 5.56.
4.1.9. 3-Methyl-5-(4-methylphenyl)oxazolidin-2,4-dione
(5i). Colorless solid (63%). Mp 111 8C (THF–Et2O); IR
1
(KBr) nZ1805, 1734 cmK1; H NMR (CDCl3) d (ppm):
4.2.2. N-(3-Fluorophenyl)-2-hydroxy-2-(1-naphthyl)-
acetamide (6b). Parameter A. Colorless solid (91%). Mp
2.37 (s, 3H), 3.13 (s, 3H), 5.71 (s, 1H), 7.20 (d, JZ8.13 Hz,
2H), 7.30 (d, JZ8.13 Hz, 2H); 13C NMR (CDCl3) d (ppm):
21.7, 26.6, 80.9, 126.4, 128.9, 130.2, 140.4, 155.8, 171.8.
Anal. Calcd for C11H11NO3: C, 64.38; H, 5.40; N, 6.83.
Found: C, 64.25; H, 5.43; N, 6.80.
175 8C (Et2O–hexane); IR (KBr) nZ3302, 3229, 1655 cmK1
;
1H NMR (CDCl3) d (ppm): 3.51 (s, 1H), 5.83 (s, 1H), 6.81
(t, JZ8.41 Hz, 1H), 7.11 (d, JZ9.16 Hz, 1H), 7.20–7.27
(m, 1H), 7.46–7.62 (m, 5H), 7.89–7.92 (m, 2H), 8.12 (s,
1H), 8.19 (d, JZ8.41 Hz, 1H); 13C NMR (CDCl3) d (ppm):
80.3, 113.4, 113.6, 116.4, 116.6, 121.4, 126.4, 129.7, 130.5,
130.9, 131.1, 131.6, 132.4, 132.5, 153.8, 161.8, 164.3,
170.0. Anal. Calcd for C18H14FNO2: C, 73.21; H, 4.78; N,
4.74. Found: C, 73.21; H, 4.79; N, 4.86.
4.2. Microwave-assisted synthesis of 6a–i
Compound 5a–i (0.5 mmol) and sodium methoxide
(0.1 mmol) were weighed in a 10 mL glass pressure
microwave tube equipped with a magnetic stirrer bar.
Methanol (5 mL) was added, the tube was closed with a
silicon septum and the reaction mixture was subjected to
microwave irradiation for the indicated time (Table 2) using
parameters A and B. The reaction mixture was allowed to
cool to room temperature and transferred to a round bottom
flask. The solvent was evaporated, water (0.5 mL) was
added and the mixture was treated thrice with dichloro-
methane (15 mL). The combined extracts were dried over
MgSO4 and the solution was concentrated to 0.5 mL.
Addition of Et2O and hexane provided 6a–i as solid
compounds.
4.2.3. N-(4-Cyanophenyl)-2-cyclopropyl-2-hydroxy-
acetamide (6c). Parameter A. Colorless solid (87%). Mp
120 8C (Et2O–hexane); IR (KBr) nZ3462, 3317, 2218,
1690 cmK1; 1H NMR (CDCl3) d (ppm): 0.69–0.78 (m, 4H),
1.20–1.28 (m, 1H), 2.80 (s, 1H), 3.72 (d, JZ7.89 Hz, 1H),
7.63 (d, JZ8.65 Hz, 2H), 7.75 (d, JZ8.65 Hz, 2H), 8.62 (s,
1H); 13C NMR (CDCl3) d (ppm): 2.6, 3.4, 16.3, 76.0, 107.7,
119.2, 120.0, 133.8, 141.8, 171.8. Anal. Calcd for
C12H12N2O2: C, 66.65; H, 5.59; N, 12.95. Found: C,
66.43; H, 5.72; N, 12.89.
4.2.4. 2-Hydroxy-2-(2-thienyl)-N-(4-trifluoromethyl-
phenyl)acetamide (6d). Parameter A. Colorless solid
(80%). Mp 196 8C (Et2O–hexane); IR (KBr) nZ3292,
3111, 1670 cmK1; 1H NMR (CDCl3) d (ppm): 3.35 (s, 1H),
5.63 (s, 1H), 7.04 (t, JZ3.56 Hz, 1H), 7.23 (d, JZ3.31 Hz,
1H), 736 (d, JZ5.09 Hz, 1H), 7.60 (d, JZ8.65 Hz, 2H),
7.70 (d, JZ8.65 Hz, 2H), 8.41 (s, 1H); 13C NMR (CDCl3) d
(ppm): 71.3, 119.9, 126.8, 127.1, 127.6, 130.7, 137.1, 138.4,
140.7, 172.1. Anal. Calcd for C13H10F3NO2S: C, 51.83; H,
3.35; N, 4.65; S, 10.64. Found: C, 51.75; H, 3.21; N, 4.50; S,
10.49.
Parameters A. For compounds 6a–g: Discover mode;
power: 200 W; ramp time: 30 s; hold time: as indicated in
Table 2; temperature: 100 8C; pressure: 12 bar; PowerMax-
cooling.
Parameters B. For compound 6h,i: Discover mode, power:
250 W; ramp time: 30 s; hold time: as indicated in Table 2;
temperature: 150 8C; pressure: 15 bar, PowerMax-cooling.
Synthesis of 6a,h in a sealed tube. Sodium methoxide
(0.1 mmol) was added to a stirred solution of 5a,h
(0.5 mmol) in methanol (5 mL). After being refluxed at
105 8C in a sealed tube for the indicated time (Table 2), the
solvent was evaporated, water (0.5 mL) was added and the
mixture was extracted thrice with dichloromethane (15 mL).
The combined extracts were dried over MgSO4 and the
4.2.5. N-(4-Bromophenyl)-2-(2-furyl)-2-hydroxyaceta-
mide (6e). Parameter A. Colorless solid (92%). Mp
162 8C (Et2O–hexane); IR (KBr) nZ3281, 3163,
1651 cmK1 1H NMR (CDCl3) d (ppm): 3.34 (s, 1H),
;
5.29 (s, 1H), 6.40 (dd, JZ3.31, 1.78 Hz, 1H), 6.55 (d,

T. Kurz, K. Widyan / Tetrahedron 61 (2005) 7247–7251
7251
JZ3.31 Hz, 1H), 7.44–7.49 (m, 5H), 8.24 (s, 1H); 13C NMR
(CDCl3) d (ppm): 68.8, 109.7, 111.3, 117.9, 121.9, 132.5,
140.0, 174.6. Anal. Calcd for C12H10BrNO3: C, 48.67; H,
3.40; N, 4.73. Found: C, 48.52; H, 3.51; N, 4.75.
2. Sheppard, J. W.; Wang, J.; Kawai, M.; BaMaung, N. Y.; Craig,
R. A.; Erickson, A.; Lynch, L.; Patel, J.; Yang, F.; Searle,
X. B.; Lou, P.; Park, C.; Kim, K. H.; Henkin, J.; Lesniewski, R.
Bioorg. Med. Chem. Lett. 2004, 14, 865.
3. Thompson, A. M.; Blunt, J. W.; Munro, M. H. G.; Perry, N. B.;
Pannell, L. K. J. Chem. Soc., Perkin Trans. 1 1992, 1335 and
references therein.
4.2.6. N-(4-Chlorophenyl)-2-cyclohexyl-2-hydroxyaceta-
mide (6f). Parameter A. Colorless solid (84%). Mp 145 8C
1
(Et2O–hexane); IR (KBr) nZ3315, 3111, 1641 cmK1; H
4. Menendez, J. C.; Villacampa, M.; Sollhuber, M. M.
Heterocycles 1991, 32, 469.
NMR (CDCl3) d (ppm): 1.10–1.33 (m, 5H), 1.65–1.81 (m,
5H), 1.91–1.97 (m, 1H), 2.37 (s, 1H), 4.09 (d, JZ3.31 Hz,
1H), 7.29 (d, JZ8.90 Hz, 2H), 7.57 (d, JZ8.90 Hz, 2H),
8.44 (s, 1H); 13C NMR (CDCl3) d (ppm): 26.2, 26.3, 26.4,
26.7, 30.0, 42.1, 77.1, 121.4, 129.5, 129.9, 136.2, 171.6.
Anal. Calcd for C14H18ClNO2: C, 62.80; H, 6.78; N, 5.23.
Found: C, 62.60; H, 6.89; N, 5.17.
5. Lai, J. Y.; Shi, X. X.; Gong, Y. S.; Dai, L. X. J. Org. Chem.
1993, 58, 4775.
6. Wipf, P.; Kim, H. J. Org. Chem. 1993, 58, 5592.
7. Khalaj, A.; Nahid, E. Synthesis 1985, 1153.
8. Matsumoto, K.; Hashimoto, S.; Otani, S. Angew. Chem. 1986,
98, 569.
9. Solladie-Cavallo, A.; Benchegroin, M. J. Org. Chem. 1992,
57, 5831.
4.2.7. N-Cyclopropyl-2-hydroxy-2-(1-naphthyl)aceta-
mide (6g). Parameter A. Colorless solid (82%). Mp
103 8C (Et2O–hexane); IR (KBr) nZ3315, 3111,
10. Kiely, D. E.; Naiva, J. L. Tetrahedron Lett. 1991, 32, 3859.
11. Kelly, S. E.; LaCour, T. G. Synth. Commun. 1992, 22(6), 859.
12. Shin, J. M.; Kim, Y. H. Tetrahedron Lett. 1986, 27, 1921.
13. Adamczyk, M.; Grote, J.; Rege, S. Tetrahedron: Asymmetry
1997, 8, 2509.
1641 cmK1 1H NMR (CDCl3) d (ppm): 0.31–0.72 (m,
;
4H), 2.68–2.70 (m, 1H), 3.46 (s, 1H), 5.49 (s, 1H), 6.05 (s,
1H), 7.43–7.62 (m, 4H), 7.86 (t, JZ8.64 Hz, 2H), 8.06 (d,
JZ6.11 Hz, 1H); 13C NMR (CDCl3) d (ppm): 6.8, 7.1, 23.1,
73.3, 124.2, 125.7, 126.5, 127.2, 127.4, 129.3, 130.1, 131.5,
134.7, 134.9, 174.6. Anal. Calcd for C15H15NO2: C, 74.67;
H, 6.27; N, 5.80. Found: C, 74.60; H 6.15; N, 5.90.
14. (a) Soai, K.; Komiya, K.; Shigematsu, Y.; Hasegawa, H.;
Ookawa, A. J. Chem. Soc., Chem. Commun. 1982, 1282. (b)
Soai, K.; Hasegawa, H. J. Chem. Soc., Perkin Trans. 1 1985,
769. (c) Solodin, I.; Goldberg, Y.; Zelcans, G.; Lukevics, E.
J. Chem. Soc., Chem. Commun. 1990, 1321.
4.2.8.
N-(4-Fluorobenzyl)-2-hydroxy-2-(4-methyl-
15. Kawanami, Y.; Fujita, I.; Taniguchi, Y.; Katsuki, T.;
Yamaguchi, M. Chem. Lett. 1987, 2021.
phenyl)acetamide (6h). Parameter B. Colorless solid
(73%). Mp 125 8C (Et2O–hexane); IR (KBr) nZ3134,
3132, 1651 cmK1; 1H NMR (CDCl3) d (ppm): 2.34 (s, 3H),
3.44 (s, 1H), 4.38 (m, 2H), 5.01 (s, 1H), 6.65 (s, 1H), 6.97 (t,
JZ8.65 Hz, 2H), 7.13–7.17 (m, 4H), 7.26 (d, JZ8.14 Hz,
2H); 13C NMR (CDCl3) d (ppm): 21.6, 43.2, 74.5, 115.9,
116.1, 127.2, 129.7, 129.8, 130.0, 134.0, 136.8, 139.1,
163.8, 172.7. Anal. Calcd for C16H16FNO2: C, 70.32; H,
5.90; N, 5.12. Found: C, 70.19; H, 5.77; N, 5.10.
16. Fujisawa, T.; Ukaji, Y.; Funabora, M.; Yamashita, M.; Sato, T.
Bull. Chem. Soc. Jpn. 1990, 63, 1984.
17. Harada, K.; Munegumi, T. Bull. Chem. Soc. Jpn. 1984, 57,
3203.
´
18. Concellon, J. M.; Bardales, E. Org. Lett. 2003, 25, 4783.
19. Katritzky, A. R.; He, H. Y.; Susuki, K. J. Org. Chem. 2000, 65,
8210.
20. Toyooka, K.; Yoshiyuki, T.; Kubota, S. Heterocycles 1989, 29,
965.
4.2.9. 2-Hydroxy-N-methyl-2-(4-methylphenyl)aceta-
mide (6i). Parameter B. Colorless solid (55%). Mp 96 8C
21. Khalaj, A.; Nahid, E. J. Chem. Soc., Chem. Commun. 1985,
1153.
1
(Et2O–hexane); IR (KBr) nZ3337, 3198, 1655 cmK1; H
22. (a) Clark-Lewis, J. W. Chem. Rev. 1958, 58, 63. (b) Shapiro,
S. L.; Rose, I. M.; Testa, F. C.; Roskin, E.; Freedmann, L.
J. Am. Chem. Soc. 1959, 81, 6498.
NMR (CDCl3) d (ppm): 2.34 (s, 3H), 2.80 (d, JZ4.80 Hz,
3H), 3.45 (s, 1H), 4.97 (s, 1H), 6.21 (s, 1H), 7.17 (d, JZ
8.13 Hz, 2H), 7.26 (d, JZ8.13 Hz, 2H); 13C NMR (CDCl3)
d (ppm): 21.6, 26.7, 74.4, 127.2, 129.90, 129.93, 136.9,
138.9, 173.5. Anal. Calcd for C10H13NO2: C, 67.02; H, 7.31;
N, 7.81. Found: C, 67.13; H, 7.20; N, 7.85.
´
´
´
23. Benavides, A.; Martınez, R.; Jimenez- Vazquez, H. A.;
Delgado, F.; Tamariz, J. Heterocycles 2001, 55, 469.
24. Frank, M.; Miethchen, R. Carbohydr. Res. 1998, 313, 49.
25. (a) Kurz, T.; Widyan, K. Org. Biomol. Chem. 2004, 2, 2023.
(b) Kurz, T.; Widyan, K. Org. Lett. 2004, 6, 4403. (c) Kurz, T.;
Widyan, K. J. Org. Chem. 2005, 70, 3108.
26. (a) Tomlin, C. D. S. The Pesticide Manual, 12th ed. British
Crop Protection Council: Farnham, Surrey, 2000; p. 375. (b)
Tomlin, C. D. S. The Pesticide Manual, 12th ed. British Crop
Protection Council: Farnham, Surrey, 2000; p. 956. (c)
Thueson, D.O.; Withrow, C. D.; Giam, C. S.; Woodbury, D.
M. Epilepsia 1974, 15, 563.
References and notes
1. Ahmad, A.; Ashfaq, A.; Alam, M.; Bisacchi, G. S.; Chen, P.;
Cheng, P. T. W.; Greytok, J. A.; Hermsmeier, M. A.; Lin, P. F.;
Lis, K. A.; Merchant, Z.; Mitt, T.; Skoog, M.; Spergel, S. H.;
Tino, J. A.; Vite, G. D.; Colonno, R. J.; Zahler, R.; Barrish,
J. C. Bioorg. Med. Chem. Lett. 1995, 5, 1729.
27. Gassman, P. G.; Talley, J. J. Tetrahedron Lett. 1978, 40, 3773.