O-Protected 3-hydroxy-oxazolidin-2,4-diones: Novel precursors in the synthesis of α-hydroxyhydroxamic acids

Article abstract of DOI:10.1039/b404950k

O-Protected 3-hydroxyoxazolidin-2,4-diones have been prepared in a novel one-pot reaction by subsequent treatment of cyanohydrins with 1,1′-carbonyldiimidazole and O-protected hydroxylamines followed by acidic hydrolysis of the intermediate 4-imino-oxazolidin-2-ones. Decarbonylation of O-protected 3-hydroxyoxazolidin-2,4-diones by catalytic amounts of sodium methoxide, lithium hydroxide, sodium carbonate and caesium carbonate in methanol afforded O-protected α-hydroxyhydroxamic acids in excellent yields. Their deprotection provided a series of novel α-hydroxyhydroxamic acids.

Full text of DOI:10.1039/b404950k

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O-Protected 3-hydroxy-oxazolidin-2,4-diones: novel precursors
in the synthesis of ꢀ-hydroxyhydroxamic acids
Thomas Kurz* and Khalid Widyan
Institute of Pharmacy, University of Hamburg, Bundesstrasse 45, 20146 Hamburg, Germany.
E-mail: kurz@chemie.uni-hamburg.de; Fax: ϩ4940428386573; Tel: ϩ4940428383467
Received 1st April 2004, Accepted 28th May 2004
First published as an Advance Article on the web 21st June 2004
O-Protected 3-hydroxyoxazolidin-2,4-diones have been prepared in a novel one-pot reaction by subsequent treatment
of cyanohydrins with 1,1Ј-carbonyldiimidazole and O-protected hydroxylamines followed by acidic hydrolysis of
the intermediate 4-imino-oxazolidin-2-ones. Decarbonylation of O-protected 3-hydroxyoxazolidin-2,4-diones by
catalytic amounts of sodium methoxide, lithium hydroxide, sodium carbonate and caesium carbonate in methanol
afforded O-protected α-hydroxyhydroxamic acids in excellent yields. Their deprotection provided a series of novel
α-hydroxyhydroxamic acids.
described conversion of O-substituted 3-hydroxyoxazolidin-
2,4-diones (6) into 7 has not been reported before. Especially
the conversion of a 5,5-disubstituted 3-cyclohexyl-oxazolidin-
2,4-dione into the corresponding α-hydroxycarboxamide,
Introduction
α-Hydroxyhydroxamic acids are important derivatives of
hydroxamic acids, a class of compounds which displays a broad
range of biological activities. Due to the ability of hydroxamic
acids to act as chelators for a variety of different metal cations
reported by Miethchen and Frank, by refluxing the oxazolidin-
2,4-dione in methanol in the presence of an excess of sodium
the hydroxamate functionality represents a key pharmacophore
methoxide for seven hours attracted our interest.21
in the development of metalloenzyme inhibitors.1–3
α-Hydroxyhydroxamates, such as Marimastat and some
Results and discussion
analogues, have attracted considerable interest in medicinal
chemistry as matrix metalloproteinase (MMP) inhibitors.1,2
Furthermore, O-substituted α-hydroxyhydroxamic acids have
found wide applications as building blocks for the synthesis of
various heterocycles.4–7
Due to the diprotic nature of hydroxamic acids, the
hydroxamate functionality is often introduced into a molecule
in a protected form.8 In most cases only the hydroxamic acid
hydroxy group is protected. Among various protecting groups
used in hydroxamic acid chemistry the O-benzyl group is one
of the most widely used.9 O-Benzylhydroxamates are readily
deprotected under mild conditions in high yields by catalytic
hydrogenation on Pd–C. Other common protecting groups are
for instance O-t-Bu,10 O-TMS,11 and O-3,4-dimethoxybenzyl
(DMB).12
Synthesis of O-protected 3-hydroxyoxazolidin-2,4-diones (6)
Cyanohydrins (2) have been prepared by reactions of aldehydes
(1) with trimethylsilyl cyanide in almost quantitative yields
according to an established literature procedure.22 Treatment of
2 with CDI in dry dichloromethane at ambient temperature
led to imidazolide intermediates 3, which after addition of
O-protected hydroxylamines in turn underwent hydroxyl-
aminolysis to the corresponding carbamate intermediates 4.
Ring closure of 4 furnished 4-imino-oxazolidin-2-ones (5),
which are characterised by two sharp IR-absorptions bands
at 1690–1700 cmϪ1 (C᎐N) and 1790–1805 cmϪ1 (C᎐O).
᎐
᎐
Subsequent acidic hydrolysis of 5 afforded 6 in overall high
yield of 80–92% (Scheme 1).
Compounds 6 have previously been prepared in moderate to
good yields by subsequent treatment of α-hydroxy-carboxylic
Various synthetic methods exist for preparation of
hydroxamic acids and their O-protected derivatives. Classically,
O-protected hydroxamic acids are prepared by reacting
O-protected hydroxylamines with activated carboxylic acids
derivatives (e.g. acid halides, anhydrides). Because of the
importance of the hydroxamic acid functionality a variety of
novel methods for the preparation of hydroxamic acids, starting
from substituted hydroxylamines and N-acyloxyoxazolidi-
nones, N-acyl-benzotriazoles or 2-acyloxypyridines, have been
developed in recent years.13–15 Although the methods described
above are quite efficient in the preparation of hydroxamic
acids the synthesis of α-hydroxyhydroxamic acids and their
O-protected derivatives is still difficult and yields are often low.
Relatively few synthetic methods exist for the preparation
of compounds 7. Most of the publications relate to coupling
reactions of α-hydroxycarboxylic acids with O-protected
hydroxylamines in the presence of carbodiimides.16,17 We know
of only one article describing a 1,1Ј-carbonyldiimidazole (CDI)
mediated synthesis of an O-protected α-hydroxyhydroxamic
acid in 18% yield.18 Just one author refers to a BOP/HOBT
coupling procedure for the synthesis of O-protected α-hydroxy-
hydroxamates.19
In contrast to the well known synthesis of α-hydroxycarb-
Scheme 1 Reagents and Conditions. i, TMSCN, HCl; ii, CDI; iii,
H2NOR2; iv, THF, HCl.
oxamides from 3-alkyl(aryl)-oxazolidin-2,4-diones,20 the herein
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 0 2 3 – 2 0 2 7
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Table
1
Conversion of 5-benzyl-3-benzyloxy-oxazolidin-2,4-dione
(6a) into N-benzyloxy-2-hydroxy-3-phenyl-propionamide (7a)
Table
2 Isolated yields of O-protected 3-hydroxyoxazolidin-2,4-
diones (6) and α-hydroxyhydroxamic acids (7, 8)
Basea
Equivalents
Yield (%)
Time/h
Entry
R1
R2
Yield (%)
CH3ONa
CH3ONa
CH3ONa
CH3ONa
C2H5ONa
Cs2CO3
4.44
0.44
0.22
0.11
0.10
0.20
0.20
0.20
88
90
92
87
80
66
78
80
1
1
1
1.5
1
3
3
3
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
8d
8e
8h
8i
C6H5CH2
C6H5
CH3
(CH3)2CH
(CH3)3C
C3H5
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
3,4-di-(CH3O)-C6H3CH2
C6H5
92
85
85
90
85
80
90
83
85
80
81
83
92
89
92
89
88
86
91
91
86
83
87
88
90
91
92
93
Na2CO3
LiOH
C6H11
C6H CH2CH2
5
(C6H5)2CH
(C6H5)2CH
(C6H5)2CH
(C6H5)2CH
C6H5CH2
C6H5
CH3
(CH3)2CH
(CH3)3C
a 1 mmol of 6a was reacted with the appropriate base in 30 mL of
methanol.
(CH3)3
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
3,4-di-(CH3O)-C6H3CH2
C6H5
acid esters with 1,1Ј-carbonyl-di-(1,2,4-triazole) and hydroxyl-
amines,23 by carbonylation of O-substituted α-hydroxy-
hydroxamic acids4 and by reactions of 1,2,5-dioxazian-3,6,-
diones with O-substituted hydroxylamines.24
C3H5
C6H11
Decarbonylation of O-protected 3-hydroxy-oxazolidin-2,4-
diones (6)
C6H5CH2CH2
(C6H5)2CH
(C6H5)2CH
(C6H5)2CH
(C6H5)2CH
(CH3)2CH
C3H5
Next we investigated the reactions of 6a with various bases in
methanol (Table 1). Refluxing of 6a in methanol in the presence
of sodium methoxide (0.22 equivalent) for 1 h afforded 7a in
excellent yield of 92% (Scheme 2). When 6a was treated with
sodium ethoxide (0.1 equivalent) under similar conditions 7a
was obtained in somewhat lower yields of 80%. Reactions of
6a with caesium carbonate, sodium carbonate and lithium
hydroxide in methanol at room temperature furnished 7a in
moderate to good yields of 66–80%. Even the treatment of 6a
with an excess of sodium methoxide (4.44 equivalent) provided
7a in high yield (Table 1).
(CH3)3
H
H
H
C6H5CH2CH2
(C6H5)2CH
H
presence of different bases in methanol. Finally, deprotection
of 7 led to novel α-hydroxyhydroxamic acids (8). We have
demonstrated that O-protected 3-hydroxyoxazolidin-2,4-diones
are valuable precursors in the preparation of O-protected
α-hydroxyhydroxamic acids. The oxazolidin-2,4-dione ring
system serves as protecting group for the alcoholic hydroxyl
group and for the hydroxamic acid nitrogen. For medicinal and
organic chemists this method offers novel synthetic options in
the preparation of α-hydroxyhydroxamic acids (6, 7).
Scheme 2 Reagents and Conditions. i, 0.22 equi. NaOMe, MeOH,
reflux.
Experimental
Melting points (uncorrected) were determined on a Mettler
FP 62 apparatus. Elemental analyses were carried out with a
Heraeus CHN-O-Rapid instrument. IR spectra were recorded
Finally, catalytic hydrogenation of 7d, e, h, i on Pd–C in
methanol provided the novel α-hydroxyhydroxamic acids (8d, e,
h, i) in high yields of 90–93%. Deprotection of O-3,4-dimeth-
oxybenzyl hydroxamate 7j by DDQ led to 8i in only 30% yield
(Scheme 3). All attempts to synthesise 8i from 7i using TFA/
DCM were unsuccessful.
on a Shimadzu FT-IR 8300. H NMR (400 MHz) and 13C
1
NMR (100 MHz) spectra were recorded on a Bruker AMX 400
spectrometer using tetramethylsilane as an internal standard
and DMSO-d6 as a solvent. Cyanohydrins (2) have been
prepared according to an established literature procedure
and were used immediately after characterisation by IR
spectroscopy.23
General procedure for the preparation of 6a–l
A solution of cyanohydrine (6 mmol) in dry CH2Cl2 (5 mL)
was added dropwise over a period of 10 min to a suspension of
1,1Ј-carbonyldiimidazole (6.5 mmol) in dry CH2Cl2 (6 mL)
under ice cooling. After stirring at room temperature for
10 min, the appropriate hydroxylamine (6 mmol) was added
and the reaction mixture was stirred at room temperature for
45–60 min. The solvent was removed under reduced pressure
and the residue was dissolved in THF (3 mL). Hydrochloric
acid (10 mL, 20%) was added under ice cooling and the mixture
was stirred again for 30 min. The reaction mixture was
extracted twice with EtOAc and the combined extracts were
dried over MgSO4. Removal of the solvent under reduced
pressure afforded oily residues, which were crystallised
from EtOAc–hexane to give 6a–l as colourless solids. Table 2
summarises the isolated yields of 6, 7 and 8.
Scheme 3 Reagents and Conditions. i, H2, Pd–C, or DDQ.
The structures of the novel compounds were confirmed by
IR, 1H, 13C NMR spectroscopy and elemental analysis.
Conclusions
In conclusion, we have developed a novel and convenient
synthetic pathway for the preparation of O-protected
α-hydroxyhydroxamic acids (7), starting from various aldehydes
in 66–84% overall yield. Our method includes an operationally
simple one pot-synthesis for the preparation of O-protected
3-hydroxyoxazolidin-2,4-diones (6) and the previously
unreported decarbonylation of 6 under mild conditions in the
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 0 2 3 – 2 0 2 7
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5-Benzyl-3-benzyloxy-oxazolidin-2,4-dione, 6a
2H), 4.85 (q, J = 10.43 Hz, 2H), 4.90 (q, J = 7.63 Hz, 1H),
7.21–7.41 (m, 10H); δC(DMSO-d6) 30.48, 33.47, 77.32, 79.30,
126.45, 128.65, 128.79, 129.60, 129.95, 130.01, 133.63, 134.40,
151.35, 166.85.
(1.65 g, 92%) as colourless solid, mp 139 ЊC (from EtOAc–
hexane). (Found: C, 68.43; H, 5.08; N, 4.90. C17H15NO4
requires C, 68.68; H, 5.09; N, 4.71%); νmax(KBr)/cmϪ1 1827,
1751; δH(DMSO-d6) 3.11–3.27 (m, 2H), 4.85 (q, J = 10.43 Hz,
2H), 5.35 (q, J = 4.58 Hz, 1H), 7.22–7.41 (m, 10H); δC(DMSO-
d6) 35.83, 78.37, 79.27, 127.63, 128.82, 128.89, 129.66, 129.97,
130.01, 133.63, 134.39, 151.38, 166.91.
5-Benzhydryl-3-benzyloxy-oxazolidin-2,4-dione, 6i
(1.79 g, 80%) as colourless solid, mp 125 ЊC (from EtOAc–
hexane). (Found C, 73.98; H, 5.13; N, 3.75. C23H19NO4 requires
C, 73.78; H, 5.00; N, 3.80%); νmax(KBr)/cmϪ1 1825, 1755;
δH(DMSO-d6) 4.67 (q, J = 10.18 Hz, 2H), 4.75 (d, J = 4.57 Hz,
1H), 5.92(d, J = 4.58Hz, 1H), 7.21–7.40 (m, 15H); δC(DMSO-
d6) 74.16, 79.31, 79.80, 126.59, 127.45, 128.56, 128.93, 129.45,
129.96, 137.91, 141.59, 150.81, 166.26.
3-Benzyloxy-5-phenyl-oxazolidin-2,4-dione, 6b
(1.45 g, 85%) as colourless solid, mp 90 ЊC (from EtOAc–
hexane). (Found: C, 67.78; H, 4.60; N, 5.09. C16H13NO4
requires C, 67.84; H, 4.63; N, 4.94%); νmax(KBr)/cmϪ1 1817,
1751; δH(DMSO-d6) 4.96 (q, J = 10.43 Hz, 2H), 5.46 (s, 1H),
7.35–7.48 (m, 10H); δC(DMSO-d6) 78.37, 79.27, 127.63, 128.82,
128.89, 129.66, 129.97, 130.01, 133.63, 134.39, 151.38, 166.91.
5-Benzyhydryl-3-(3,4-dimethoxy-benzyloxy)-oxazolidin-2,4-
dione, 6j
(2.08 g, 80%) as colourless solid, mp 118 ЊC (from EtOAc–
hexane). (Found: C, 69.19; H, 5.39; N, 3.31. C25H23NO6
requires C, 69.27; H, 5.35; N, 3.23%); νmax(KBr)/cmϪ1 1825,
1750; δH(DMSO-d6) 3.74 (s, 3H), 3.76 (s, 3H), 4.62 (q, J = 9.92
Hz, 2H), 4.68 (d, J = 4.58 Hz, 1H), 5.93 (d, J = 4.58 Hz, 1H),
6.82–6.97 (m, 3H), 7.25–7.80 (m, 10H); δC(DMSO-d6) 51.10,
55.81, 55.80, 79.31, 79.69, 111.72, 113.53, 123.02, 125.64,
127.47, 127.88, 128.59, 128.91, 129.36, 137.97, 139.53, 148.89,
150.04, 151.28, 166.29.
3-Benzyloxy-5-methyl-oxazolidin-2,4-dione, 6c
(1.13 g, 85%) as colourless solid, mp 69 ЊC (from EtOAc–
hexane). (Found: C, 59.81; H, 5.15; N, 6.20. C11H11NO4
requires C, 59.73; H, 5.01; N, 6.33%); νmax(KBr)/cmϪ1 1825,
1750; δH(DMSO-d6) 1.44 (d, J = 6.87 Hz, 3H), 5.10 (q, J = 7.12
Hz, 1H), 5.14 (q, J = 10.43 Hz, 2H), 7.40–7.50 (m, 5H);
δC(DMSO-d6) 16.05, 75.05, 79.14, 128.87, 129.65, 130.13,
133.82, 151.58, 168.38.
3-Benzyloxy-5-isopropyl-oxazolidin-2,4-dione, 6d
5-Benzhydryl-3-phenoxy-oxazolidine-2,4-dione, 6k
(1.34 g, 90%) as colourless solid, mp 60 ЊC (from EtOAc–
hexane). (Found: C, 62.64; H, 6.07; N, 5.62. C13H15NO4
requires C, 62.75; H, 6.15; N, 5.53%); νmax(KBr)/cmϪ1 1825,
1750; δH(DMSO-d6) 0.80 (d, J = 6.85 Hz, 3H), 0.82 (d, J = 6.85
Hz, 3H), 1.85–1.95 (m, 1H), 4.55 (d, J = 8.91 Hz, 1H), 4.82
(s, 2H), 7.30–7.41 (m, 5H); δC(DMSO-d6) 17.01, 19.10, 31.70,
76.80, 79.45, 126.61, 127.38, 127.85, 131.55, 151.38, 166.91.
(1.75 g, 81%) as colourless solid, mp 153 ЊC (from EtOAc–
hexane). (Found: C, 73.50; H, 4.81; N, 4.01. C22H17NO4
requires C, 73.53; H, 4.77; N, 3.90%); νmax(KBr)/cmϪ1 1830,
1755; δH(DMSO-d6) 4.82 (d, J = 4.57 Hz, 1H), 6.04 (d, J = 4.58
Hz, 1H), 7.16–7.44 (m, 15H); δC(DMSO-d6) 52.49, 74.46,
112.61, 113.14, 120.91, 122.62, 126.95, 127.55, 128.82, 129.35,
129.67, 129.88, 130.28, 140.76, 153.98, 159.90.
3-Benzyloxy-5-tert-butyl-oxazolidin-2,4-dione, 6e
5-Benzhydryl-3-tert-butoxy-oxazolidine-2,4-dione, 6l
(1.35 g, 85%) as colourless solid, mp 64 ЊC (from EtOAc–
hexane). (Found: C, 63.73; H, 6.58; N, 5.53. C14H17NO4
requires C, 63.87; H, 6.51; N, 5.32%); νmax(KBr)/cmϪ1 1820,
1750; δH(DMSO-d6) 0.92 (s, 9H), 4.73 (s, 1H), 5.13 (s, 2H),
7.40–7.49 (m, 5H); δC(DMSO-d6) 24.58, 34.46, 79.01, 84.60,
128.82, 129.66, 130.10, 133.77, 151.61, 166.48.
(1.69 g, 83%) as colourless solid, mp 115 ЊC (from EtOAc–
hexane). (Found: C, 70.78; H, 6.24; N, 4.13. C20H21NO4
requires C, 70.60; H, 6.08; N, 4.01%); νmax(KBr)/cmϪ1 1820,
1745; δH(DMSO-d6) 1.15 (s, 9H), 4.70 (d, J = 4.57 Hz, 1H), 5.90
(d, J = 4.58 Hz, 1H), 7.20–7.42 (m, 10H); δC(DMSO-d6) 26.68,
52.49, 55.75, 79.80, 111.67, 112.85, 121.79, 126.44, 128.49,
129.35, 141.98, 142.30, 150.93, 166.73.
3-Benzyloxy-5-cyclopropyl-oxazolidin-2,4-dione, 6f
Synthetic procedures for preparation of 7a–l
(1.18 g, 80%) as colourless solid, mp 89 ЊC (from EtOAc–
hexane). (Found: C, 63.01; H, 5.34; N, 5.54. C13H13NO4
requires C, 63.15; H, 5.30; N, 5.66%); νmax(KBr)/cmϪ1 1825,
1753; δH(DMSO-d6) 0.41–0.68 (m, 4H), 1.17–1.26 (m, 1H), 4.55
(d, J = 8.90 Hz, 1H), 5.13 (q, J = 10.43 Hz, 2H), 7.41–7.60
(m, 5H); δC(DMSO-d6) 8.87, 27.60, 76.83, 79.46, 126.61,
127.38, 127.85, 131.55, 149.27, 164.55.
A: General procedure; using sodium methoxide. To a stirred
solution of 6a–l (1 mmol) in methanol (30 mL) was added
NaOMe (0.22 mmol) and the reaction mixture was refluxed
for 1 h. The reaction mixture was concentrated in vacuo, water
(15 mL) was added and the mixture was extracted with EtOAc.
The combined extracts were dried over MgSO4 and the solvent
was removed under reduced pressure. Recrystallisation of
the remaining solids from EtOAc–hexane provided 7a–l as
colourless solids.
3-Benzyloxy-5-cyclohexyl-oxazolidin-2,4-dione, 6g
(1.56 g, 90%) as colourless solid, mp 77 ЊC (from EtOAc–
hexane). (Found: C, 66.60; H, 6.64; N, 4.91. C16H19NO4
requires C, 66.42; H, 6.62; N, 4.84%); νmax(KBr)/cmϪ1 1817,
1757; δH(DMSO-d6) 0.94–1.34 (m, 6H), 1.68–1.85 (m, 5H), 4.87
(d, J = 4.58 Hz, 1H), 5.14 (q, J = 10.43 Hz, 2H), 7.40–7.48
(m, 5H); δC(DMSO-d6) 25.30, 25.45, 25.69, 25.83, 27.41, 38.69,
78.98, 81.69, 128.81, 129.65, 130.18, 133.73, 151.80, 166.86.
B: Synthesis of 7a using sodium ethoxide. To a stirred solution
of 6a (1 mmol) in methanol (30 ml) was added NaOEt
(0.1 mmol) and the mixture was refluxed for 1 h. The solvent
was evaporated, water (15 mL) was added and the mixture was
extracted with EtOAc. The combined extracts were dried over
MgSO4 and the solvent was removed under reduced pressure.
Recrystallisation of the remaining solid from EtOAc–hexane
provided 7a as a colourless solid.
3-Benzyloxy-5-phenethyl-oxazolidin-2,4-dione, 6h
(1.55 g, 83%) as colourless solid, mp 120 ЊC (from EtOAc–
hexane). (Found: C, 69.40; H, 5.58; N, 4.45. C18H17NO4
requires C, 69.44; H, 5.50; N, 4.50%); νmax(KBr)/cmϪ1 1830,
1750; δH(DMSO-d6) 1.82–2.10 (m, 2H), 2.60 (t, J = 8.14 Hz,
C: Synthesis of 7a using caesium carbonate, sodium carbonate
and lithium hydroxide. To a stirred solution of 6a (1 mmol) in
methanol (30 mL) was added the appropriate base (0.2 mmol)
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 0 2 3 – 2 0 2 7
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and the reaction mixture was kept at room temperature for 3 h.
After neutralization with aqueous citric acid (5%) the reaction
mixture was extracted with EtOAc and the organic layer was
dried over MgSO4. Removal of the solvent under reduced
pressure afforded 7a as a solid product, which was recrystallised
from EtOAc–hexane.
J = 5.34 Hz, 1H), 4.79 (s, 2H), 5.21 (d, J = 6.10 Hz, 1H), 7.33–
7.41 (m, 5H), 10.97 (s, 1H); δC(DMSO-d6) 25.94, 26.11, 26.28,
27.09, 29.03, 41.51, 74.66, 77.10, 128.50, 128.56, 129.04, 136.35,
170.23.
N-Benzyloxy-2-hydroxy-4-phenyl-butyramide, 7h
(0.26 g, 91%) as colourless solid, mp 98 ЊC (from EtOAc–
hexane). (Found: C, 71.28; H, 6.88; N, 5.12. C17H19NO3
requires C, 71.56; H, 6.71; N, 4.91%); νmax(KBr)/cmϪ1 1645;
δH(DMSO-d6) 1.72–1.91 (m, 2H), 2.60 (t, J = 7.63 Hz, 2H), 3.90
(m, 1H), 4.80 (s, 2H), 5.48 (d, J = 5.85 Hz, 1H), 7.15–7.42
(m, 10H), 11.09 (s, 1H); δC(DMSO-d6) 30.97, 36.54, 69.91,
77.08, 126.08, 128.52, 128.58, 128.66, 129.05, 136.34, 142.05,
170.80.
N-Benzyloxy-2-hydroxy-3-phenyl-propionamide, 7a
(0.25 g, 92%) as colourless solid, mp 135 ЊC (from EtOAc–
hexane). (Found: C, 70.67; H, 6.31; N, 5.23. C16H17NO3
requires C, 70.83; H, 6.32; N, 5.16%); νmax(KBr)/cmϪ1 1668;
δH(DMSO-d6) 2.74–2.95 (m, 2H), 4.10 (m, 1H), 4.71 (s, 2H),
5.50 (d, J = 6.36 Hz, 1H), 7.17–7.35 (m, 10H), 11.06 (s, 1H);
δc(DMSO-d6) 40.72, 71.55, 77.14, 126.44, 128.33, 128.55,
128.60, 129.16, 129.84, 136.25, 138.42, 170.16.
N-Benzyloxy-2-hydroxy-3,3-diphenylpropionamide, 7i
N-Benzyloxy-2-hydroxy-2-phenylacetamide, 7b
(0.30 g, 86%) as colourless solid, mp 130 ЊC (from EtOAc–
hexane). (Found: C, 76.16; H, 6.15; N, 4,14. C22H21NO3
requires C, 76.06; H, 6.09; N, 4.33%); νmax(KBr)/cmϪ1 1672;
δH(DMSO-d6) 4.34 (d, J = 10.43 Hz, 1H), 4.40 (q, J = 10.18 Hz,
2H), 4.65 (t, J = 7.37 Hz, 1H), 5.79 (d, J = 7.12 Hz, 1H), 7.10–
7.37 (m, 15H), 11.09 (s, 1H); δC(DMSO-d6) 55.76, 72.73, 77.07,
111.67, 112.85, 121.79, 126.44, 128.34, 128.49, 128.93, 129.35,
141.98, 142.30, 148.85, 149.21, 169.08.
(0.23 g, 89%) as colourless solid, mp 107 ЊC (from EtOAc–
hexane). (Found: C, 70.19; H, 6.01; N, 5.23. C15H15NO3
requires C, 70.02; H, 5.88; N, 5.44%); νmax(KBr)/cmϪ1 1672;
δH(DMSO-d6) 4.91 (d, J = 2.29 Hz, 1H), 5.45 (s, 2H), 5.92
(d, J = 3.31 Hz, 1H), 7.24–7.40 (m, 10H), 11.06 (s, 1H);
δC(DMSO-d6) 75.66, 77.14, 126.40, 128.35, 128.59, 128.66,
129.23, 129.89, 136.40, 138.49, 170.16.
N-Benzyloxy-2-hydroxy-propionamide, 7c
N-(3,4-Dimethoxy-benzyloxy)-2-hydroxy-3,3-diphenyl-propion-
amide, 7j
(0.18 g, 92%) as colourless solid, mp 59 ЊC (from EtOAc–
hexane). (Found: C, 61.44; H, 6.66; N, 7.23. C10H13NO3
requires C, 61.53; H, 6.71; N, 7.17%); νmax(KBr)/cmϪ1 1664;
δH (DMSO-d6) 1.20 (d, J = 6.87 Hz, 3H), 3.97 (m, 1H), 4.79 (s,
2H), 5.36 (d, J = 5.34 Hz, 1H), 7.32–7.42 (m, 5H), 11.01 (s, 1H);
δC(DMSO-d6) 21.32, 66.75, 77.07, 128.54, 128.60, 129.08,
136.29, 171.51.
(0.34 g, 83%) as colourless solid, mp ЊC (from EtOAc–hexane).
(Found C, 70.82; H, 6.30; N, 3,34. C24H25NO5 requires C, 70.75;
H, 6.18; N, 3.44%); νmax(KBr)/cmϪ1 1670; δH(DMSO-d6) 3.74 (s,
6H), 4.30 (d, J = 10.43 Hz, 1H), 4.36 (q, J = 10.18 Hz, 2H), 4.62
(t, J = 7.37 Hz, 1H), 5.71 (d, J = 7.12 Hz, 1H), 6.70–6.89
(m, 3H), 7.14–7.35 (m, 10H), 11.09 (s, 1H); δC(DMSO-d6)
54.34, 55.76, 72.73, 77.07, 111.67, 112.85, 121.79, 126.44,
126.63, 128.34, 128.49, 128.93, 129.35, 141.98, 142.30, 148.85,
149.21, 169.08.
N-Benzyloxy-2-hydroxy-3-methyl-butyramide, 7d
(0,20 g, 89%) as colourless solid, mp 69 ЊC (from EtOAc–
hexane). (Found: C, 64.60; H, 7.75; N, 6.11. C12H17NO3
requires C, 64.55; H, 7.67; N, 6.27%); νmax(KBr)/cmϪ1 1670;
δH (DMSO-d6) 0.80 (d, J = 6.87 Hz, 3H), 0.85 (d, J = 6.87 Hz,
3H), 1.87–1.95 (m, 1H), 3.60 (t, J = 5.85 Hz, 1H), 4.80 (s, 2H),
5.26 (d, J = 6.11 Hz, 1H), 7.31–7.42 (m, 5H), 11.00 (s, 1H);
δC(DMSO-d6) 17.07, 19.15, 31.75, 75.12, 77.11, 128.51, 128.58,
129.01, 136.37, 170.35.
2-Hydroxy-N-phenoxy-3,3-diphenyl-propionamide, 7k
(0.29 g, 87%) as colourless solid, mp 125 ЊC (from EtOAc–
hexane). (Found: C, 75.66; H, 5.74; N, 4.20. C21H19NO3
requires C, 75.45; H, 5.74; N, 4.31%); νmax(KBr)/cmϪ1 1670;
δH(DMSO-d6) 4.34 (d, J = 10.43 Hz, 1H), 4.65 (t, J = 7.37 Hz,
1H), 5.79 (d, J = 7.12 Hz, 1H), 7.07–7.40 (m, 15H), 11.01
(s, 1H); δC(DMSO-d6) 55.76, 72.73, 112.61, 113.14, 120.91,
122.62, 126.95, 127.55, 128.82, 129.35, 129.67, 129.88, 130.28,
140.76, 169.08.
N-Benzyloxy-2-hydroxy-3,3-dimethyl-butyramide, 7e
(0.21g, 88%) as colourless solid, mp 54 ЊC (from EtOAc–
hexane); (Found: C, 66.01; H, 8.19; N, 6.08C13H19NO3 requires
C, 65.80; H, 8.07; N, 5.90%); νmax(KBr)/cmϪ1 1668; δH(DMSO-
d6) 0.86 (s, 9H), 3.43 (d, J = 5.85 Hz, 1H), 4.79 (s, 2H), 5.24–5.28
(m, 1H), 7.31–7.42 (m, 5H), 10.92 (s, 1H); δC(DMSO-d6) 26.38,
34.79, 77.07, 77.60, 127.74, 128.57, 128.96, 136.44, 169.96.
N-tert-Butoxy-2-hydroxy-3,3-diphenyl-propionamide, 7l
(0.27g, 88%) as colourless solid, mp 115 ЊC (from EtOAc–
hexane). (Found: C, 72.82; H, 7.40; N, 4.47. C19H23NO3
requires C, 72.65; H, 7.28; N, 4.47%); νmax(KBr)/cmϪ1 1668;
δH(DMSO-d6) 1.18 (s, 9H), 4.35 (d, J = 10.43 Hz, 1H), 4.66
(t, J = 7.36 Hz, 1H), 5.80 (d, J = 7.13 Hz, 1H), 7.08–7.38 (m,
10H), 11.08 (s, 1H); δC(DMSO-d6) 26.70, 52.50, 55.76, 79.73,
111.68, 112.84, 121.79, 126.44, 128.49, 129.35, 141.98, 142.32,
169.01.
N-Benzyloxy-2-cyclopropyl-2-hydroxy-acetamide, 7f
(0.19 g, 86%) as colourless solid, mp 110 ЊC (from EtOAc–
hexane). (Found: C, 65.00; H, 6.75; N, 6.20. C12H15NO3
requires C, 65.14; H, 6.83; N, 6.33%); νmax(KBr)/cmϪ1 1665;
δH(DMSO-d6) 0.43–.69 (m, 4H), 1.19–1.29 (m, 1H), 4.65 (d,
J = 8.90 Hz, 1H), 4.98 (s, 2H), 5.21 (d, J = 6.00 Hz, 1H), 7.41–
7.60 (m, 5H), 11.00 (s, 1H); δC(DMSO-d6) 8.85, 27.90, 76.81,
79.47, 126.60, 127.37, 127.82, 131.55, 169.54.
General procedure for the preparation of 8d, e, h, i
7d, e, h, i, were hydrogenated in MeOH using catalytic amounts
of 10% Pd/C for 3 h. The suspension was filtered and the
solvent was evaporated to give 8d, e, h, i as colourless solids.
N-Benzyloxy-2-cyclohexyl-2-hydroxy-acetamide, 7g
2,N-Dihydroxy-3-methyl-butyramide, 8d
(0.24 g, 91%) as colourless solid, mp 112 ЊC (from EtOAc–
hexane). (Found: C, 68.55; H, 7.90; N, 5.58. C15H21NO3
requires C, 68.42; H, 8.04; N, 5.32%); νmax(KBr)/cmϪ1 1672;
δH(DMSO-d6) 1.00–1.24 (m, 5H), 1.45–1.72 (m, 6H), 3.58 (t,
(0.12 g, 90%), as colourless solid, mp 87 ЊC. (Found: C, 45.32;
H, 8.45; N, 10.65. C5H11NO3 requires C, 45.10; H, 8.33;
N, 10.52%); νmax(KBr)/cmϪ1 1670; δH(DMSO-d6) 0.80 (d, J =
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 0 2 3 – 2 0 2 7
2026

View Online
2 S. Hanessian, N. Moitessier, C. Gauchet and M. Viau, J. Med.
Chem., 2001, 44, 3066.
3 C. Apfel, D. W. Banner, D. Bur, M. Dietz, C. Hubschwerlen,
H. Locher, F. Marlin, R. Masciadri, W. Prison and H. Stadler,
J. Med. Chem., 2001, 44, 1847.
4 D. Geffken, Arch. Pharm., 1980, 313, 817.
5 D. Geffken, Chem.-Zeit., 1979, 103, 209.
6 D. Geffken and K. Strohauer, Z. Naturforsch., B: Chem. Sci., 1985,
40, 398.
7 D. Geffken and K. Strohauer, Arch. Pharm., 1986, 319, 1084.
8 S. R. Sandler, W. Karo, in Organic Functional Group Preparations,
2nd edn., ed. H. H. Wassermann, Academic Press, New York, 1989,
vol. III, pp. 482–522.
6.87 Hz, 3H), 0.87(d, J = 6.87 Hz, 3H), 1.88–1.97 (m, 1H), 3.63
(t, J = 5.86 Hz, 1H), 5.30 (d, J = 6.11 Hz, 1H), 8.71 (s, 1H), 10.50
(s, 1H); δC(DMSO-d6) 17.18, 19.25, 31.80, 75.20, 170.50.
2,N-Dihydroxy-3,3-dimethyl-butyramide, 8e
(0.13 g, 91%) as colourless solid; mp 93 ЊC. (Found: C, 49.15; H,
9.10; N, 9.40. C6H13NO3 requires C, 48.97; H, 8.90; N, 9.52%);
νmax(KBr)/cmϪ1 1667; δH(DMSO-d6) 0.9 (s, 9H), 3.50 (d, J =
5.85 Hz, 1H), 5.28 (m, 1H), 8.75 (s, 1H), 10.92 (s, 1H);
δC(DMSO-d6) 26.38, 34.80, 77.10, 170.10.
9 S. S. Nikam, B. E. Kronberg, D. R. Johnson and A. M. Doherty,
Tetrahedron Lett., 1995, 36, 197.
2,N-Dihydroxy-4-phenyl-butyramide, 8h
10 S. Hanessian and S. Johnstone, J. Org. Chem., 1999, 64, 5896.
11 M. H. Jakobsen, O. Burchardt, A. Holm and M. Medal, Synthesis,
1990, 1008.
12 Y. O. Kawa, T. Yoshioka and O. Yonemitsu, Tetrahedron Lett., 1982,
23, 885.
13 M. P. Sibi, H. Hasegawa and S. R. Ghopade, Org. Lett., 2002, 4,
3343.
14 A. R. Katritzky, N. Kirichenko and B. V. Rogovoy, Synthesis, 2003,
2777.
(0.18 g, 92%) as colourless solid, mp 145 ЊC. (Found: C, 61.65;
H, 6.83; N, 7.01. C10H13NO3 requires C, 61.53; H, 6.71; N,
7.17%); νmax(KBr)/cmϪ1 1640; δH(DMSO-d6) 1.71–1.93 (m, 2H),
2.67–2.68 (m, 2H), 3.81–3.86 (m, 1H), 5.40 (d, J = 5.85 Hz,
1H), 7.15–7.80 (m, 5H), 8.71 (s, 1H), 10.47 (s, 1H);
δC(DMSO-d6) 31.14, 36.65, 69.82, 126.07, 128.65, 128.67,
142.14, 170.55.
15 D. Geffken and M. Haerting, Synth. Commun., 1996, 26, 4153.
16 B. Barlaam, T. G. Bird, C. Lambert-van der Brempt, D. Campbell,
S. J. Foster and R. Maciewicz, J. Med. Chem., 1999, 42, 4890.
17 K. B. Moon and K. B. Sharpless, Tetrahedron Lett., 1990, 30, 4317.
18 C. Apfel, D. W. Banner, D. Bur, M. Dietz, T. Hirata,
C. Hubschwerlen, H. Locher, M. C. P. Page, W. Prison, G. Rosse and
J. L. Specklin, J. Med. Chem., 2000, 43, 2324.
19 K. A. Josef, F. W. Kauer and R. Bihovsky, Bioorg. Med. Chem. Lett.,
2001, 11, 2615.
20 S. L. Shapiro, I. M. Rose, E. Testa, E. Roskin and I. Treedman,
J. Am. Chem. Soc., 1959, 81, 6498.
2,N-Dihydroxy-3,3-diphenyl-propionamide, 8i
(0.24 g, 93%) as colourless solid, mp 175 ЊC. (Found: C, 70.15;
H, 6.01; N, 5.65. C15H15NO3 requires C, 70.02; H, 5.88; N, 5.44);
νmax(KBr)/cmϪ1 1672; δH(DMSO-d6) 4.43 (d, J = 10.43 Hz, 1H),
4.70 (t, J = 7.37 Hz, 1H), 5.79 (d, J = 7.12 Hz, 1H), 7.16–7.30
(m, 10H), 8.75 (s, 1H), 10.53 (s, 1H); δC(DMSO-d6) 55.80,
72.81, 111.67, 112.85, 121.79, 126.44, 128.49, 129.35, 141.98,
142.30, 170.10.
21 M. Frank and R. Miethchen, Carbohydr. Res., 1998, 313, 49.
22 P. G. Gassman and J. J. Talley, Tetrahedron Lett., 1978, 40, 3773.
23 T. Kurz and D. Geffken, Z. Naturforsch., B: Chem. Sci., 1999, 54b,
667.
References
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24 D. Geffken, Synthesis, 1981, 38.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 0 2 3 – 2 0 2 7
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