Synthesis of carboxylic amides by ring-opening of oxazolidinones with Grignard reagents

Article abstract of DOI:10.1039/b800849c

Treatment of N-alkyl-oxazolidin-2-ones with Grignard reagents gives tertiary carboxylic amide products. Various substituted oxazolidinones can be used as illustrated with phenyl, benzyl or isopropyl groups on the 4-position, and methyl, benzyl or p-methox

Full text of DOI:10.1039/b800849c

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of carboxylic amides by ring-opening of oxazolidinones with
Grignard reagents
David Bensa,a Iain Coldham,*a Pia Feina¨ugle,a Ravindra B. Pathaka and Roger J. Butlinb
Received 17th January 2008, Accepted 8th February 2008
First published as an Advance Article on the web 27th February 2008
DOI: 10.1039/b800849c
Treatment of N-alkyl-oxazolidin-2-ones with Grignard reagents gives tertiary carboxylic amide
products. Various substituted oxazolidinones can be used as illustrated with phenyl, benzyl or isopropyl
groups on the 4-position, and methyl, benzyl or p-methoxybenzyl groups on the 3-position (the
nitrogen atom). A selection of Grignard reagents were successful, including allyl, benzyl, alkyl and
phenyl magnesium halides. The organomagnesium species attacks the carbonyl group and promotes
ring-opening of the oxazolidinone. The product tertiary amides are useful substrates for stereoselective
transformations and were applied to a highly selective enolate alkylation and to a ring-closing
metathesis reaction to a six-membered lactam and hence a formal synthesis of the alkaloids (−)-coniine
and (+)-stenusine.
Introduction
Oxazolidin-2-ones are very important in synthetic chemistry. They
form the basis of some antibacterial agents,1 and have played
a crucial role as chiral auxiliaries in asymmetric synthesis.2 The
oxazolidin-2-one ring can act as a masked b-amino-alcohol and
has been used for the synthesis of a variety of different ring-opened
products.3,4 Typically the oxazolidin-2-one is hydrolysed to a b-
Scheme 1 Reagents and conditions: i, 2 equiv. allyl magnesium bromide,
THF, −78 ◦C, 2.5 h, 63%; PMB = p-methoxybenzyl.
Results and discussion
amino-alcohol using forcing conditions such as by refluxing with
excess hydroxide ions.3 Alternatively, but less commonly, strong
acids, trimethylsilanolate or diamines such as ethylene diamine can
be used.4 As far as we are aware, there is only a single publication
of the ring-opening of oxazolidin-2-ones with alkyllithiums,5
together with an isolated example of the use of methyllithium
to open a hindered oxazolidin-2-one.6 These methods make use of
the (weak) electrophilicity of the carbonyl group. The carbon atom
at C-5 is also electrophilic and ring-opening of oxazolidin-2-ones
at C-5 with a nucleophile is possible.7
During research on the synthesis of some alkaloids, we had
recourse to investigate the ring-opening of the oxazolidin-2-one
1 (Scheme 1).8 Treatment of this oxazolidin-2-one with allyl
magnesium bromide gave the tertiary carboxylic amide 2. To
our knowledge this is the first example of the ring-opening of
an oxazolidin-2-one with a Grignard reagent, although there is
a report of the use of a Grignard reagent to open a 6-membered
cyclic carbamate (a benzoxazinone).9 This chemistry could provide
a useful method of wide generality for ring-opening of oxazolidin-
2-ones that expands the range of carbon-based nucleophiles in
comparison to the addition of the more reactive organolithium
species.5 We therefore decided to investigate the reaction further
and report here a range of examples of this methodology.
The N-alkyl oxazolidin-2-ones 4a–f used in this chemistry were
prepared from their correspondingN-unsubstituted analogues 3a–
c (Schemes 2 and 3), themselves prepared using standard methods
as reported previously.10 The N-alkylations were performed using
sodium or potassium hydride in THF together with iodomethane,
benzyl bromide or p-methoxybenzyl chloride.11 This led to a
selection of different substrates 4a–f, including N-alkyl and N-
benzyl compounds with either alkyl (isopropyl), benzyl or phenyl
substituents at the 4-position of the oxazolidin-2-one ring. This
range of substrates was used to probe the scope of the subsequent
ring-opening reaction.
Scheme 2 Ring-opening of oxazolidinones 4a–d (see Table 1). Reagents
and conditions: i, NaH, THF, BnBr or PMBCl or MeI; ii, R3MgX, THF,
−78 ◦C.
Treatment of the oxazolidin-2-ones 4a–d with allyl, methyl, ethyl
or phenyl magnesium bromide or with benzyl magnesium chloride
gave the desired tertiary amides 5a–h (Scheme 2, Table 1). Best
yields were normally obtained by using an excess of the Grignard
aDepartment of Chemistry, University of Sheffield, Brook Hill, Sheffield,
S3 7HF, UK. E-mail: i.coldham@shef.ac.uk; Fax: +44 (0)114 222 9346;
Tel: +44 (0)114 222 9428
bAstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
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to give the product 5l. We were pleased to find that the chemistry
was also amenable to benzyl Grignard reagents (to give the tertiary
amides 5b and 5j) and with phenyl magnesium bromide (to give
5g).
The addition of the Grignard reagent to the oxazolidin-2-one
requires several hours at −78 ◦C and this presumably reflects
the poor electrophilicity of the carbonyl group. We propose that
the addition provides a tetrahedral intermediate that is relatively
stable at low temperature. This intermediate is then hydrolysed
on work up to give the desired tertiary carboxylic amide. If
the temperature of the mixture is allowed to rise then this
should enhance the rate of addition, however it also enhances
the breakdown of the tetrahedral intermediate. For example,
addition of allyl magnesium bromide at 0 ◦C gave lower yields
of the products 5, together with, in some cases, the 2,2-diallyl-
oxazolidine product (corresponding to the complete replacement
of the carbonyl oxygen of 4 by two allyl units).
Allyl magnesium bromide is a good nucleophile for this ring-
opening reaction. Insight into the mechanism of the reaction was
obtained by studying the related crotyl (but-2-enyl) magnesium
bromide as the nucleophile. The addition of this reagent to the
oxazolidin-2-one 4d gave a mixture of products, from which
the tertiary amides 6 were isolated as the major components
(Scheme 4). These products represent addition of the allyl unit
at the c- position. There was no stereoselectivity in the process
and the products 6 were formed as a mixture of stereoisomers.
Scheme 3 Ring-opening of oxazolidinones 4e–f (see Table 2). Reagents
and conditions: i, NaH, THF, MeI or allyl bromide; ii, R2MgX, THF,
−78 ◦C.
reagent (1.5–3 equiv.) in THF at low temperature (−78 ◦C),
although in some cases it was beneficial to allow the reaction
mixture to warm to room temperature slowly. The products
were purified by column chromatography and NMR spectroscopy
revealed a mixture of rotamers in all cases. The oxazolidin-2-ones
4e–f were treated with allyl, ethyl or n-hexyl magnesium bromide
or with benzyl magnesium chloride to give the related tertiary
amides 5i–m (Scheme 3, Table 2).
Some comments on the ring-opening reaction are worthy of
mention. Allyl magnesium bromide was a good nucleophile and
good yields of the products 5a, 5c, 5d, 5h and 5i were obtained. The
product 5c appeared to be unstable and visible discolouration was
observed over several hours at room temperature. Addition of allyl
magnesium bromide to the oxazolidinone 4f was more sluggish but
was improved by the addition of further excess of the Grignard
reagent (3 equiv. gave 20% yield of 5m, with 60% recovered
oxazolidin-2-one 4f but 7 equiv. of allyl magnesium bromide gave
up to 60% yield of 5m). The addition of magnesium bromide
as an alternative to activate the oxazolidinone was ineffective
in this case but did improve the yields in the reactions of alkyl
magnesium bromides. Hence MeMgBr and EtMgBr gave only
low yields (< 20%) of the products 5e, 5f and 5k in the absence of
MgBr2, but significant improvements were obtained in its presence
(Table 1, entries 5 and 6 and Table 2, entry 3). The longer chain n-
hexyl magnesium bromide was successful in the absence of MgBr2
Scheme 4 Ring-opening of oxazolidinone 4d with crotyl magnesi◦um
=
bromide. Reagents and conditions: i, MeCH CHCH2MgBr, THF, −78 C,
32%, dr 1:1.
Table 1 Ring-opening of oxazolidinones 4a–d
Entry
Starting material
Product
R1
R2
R3
Yield 5 (%)
=
1
2
3
4a
4a
4b
4c
4c
4c
4c
4d
5a
5b
5c
5d
5e
5f
iPr
CH2Ph
CH2Ph
PMB
Me
Me
Me
CH2CH CH2
CH2Ph
69
53
68
72
39
44
65
82
iPr
iPr
CH2CH CH2
=
=
4
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2CH CH2
5a
6a
7
Me
Et
Ph
5g
5h
Me
PMB
=
8
CH2CH CH2
a With added MgBr2.
Table 2 Ring-opening of oxazolidinones 4e–f
Entry
Starting material
Product
R1
R2
Yield 5 (%)
=
1
4e
4e
4e
4e
4f
5i
Me
Me
Me
Me
CH2CH CH2
CH2Ph
Et
86
70
30
52
60
2
5j
3a
4
5k
5l
5m
(CH2)5CH3
=
=
5
CH2CH CH2
CH2CH CH2
a With added MgBr2.
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The ability of allyl Grignard reagents to add at the c- position
may contribute to the enhanced reactivity of these nucleophiles,
although even simple alkyl Grignard reagents can be successful
(Tables 1 and 2).
of MgBr2. The products are tertiary carboxylic amides. These
compounds are useful in synthesis, for example as substrates
for stereoselective alkylation or for conversion to alkaloids, as
demonstrated by ring-closing metathesis to lactam products.
Tertiary carboxylic amides of b-amino-alcohols have been found
to be excellent substrates for asymmetric alkylation reactions. This
has been demonstrated using enolates of amides derived from,
for example, pseudoephedrine or phenylglycinol.12 To illustrate
this chemistry, the tertiary carboxylic amide 5h was treated
with two equivalents of LDA and LiCl, followed by alkylation
with iodomethane (Scheme 5). This gave the alkylated product
6. The diastereoselectivity in the reaction was high (dr 97:3)
and was determined by HPLC. The configuration of the major
diastereomer is expected to be that shown in structure 6, based on
related alkylations of other tertiary carboxylic amides.12
Experimental
General methods
For general experimental details, including information on solvent
purifications and the spectrometers used in this research, see
previous descriptions.18
General method for the ring-opening of N-alkyl-oxazolidin-2-ones
The Grignard reagent (3 mmol) was added to the oxazolidinone
◦
(1 mmol) in THF (5 mL) at −78 C. After 3 h, aqueous NH4Cl
(5 mL) was added, the mixture was warmed to room temperature
and was extracted with Et2O (3 × 20 mL), dried (Na2SO4) and
evaporated. Purification by column chromatography on silica,
eluting with petrol–EtOAc, gave the tertiary amide product.
N-Benzyl-N-[(S)-1-hydroxy-3-methylbutan-2-yl]-but-3-enamide
5a. Using the general method, allyl magnesium bromide and
the oxazolidinone 4a gave the amide 5a (0.18 g, 69%) as an oil
as a mixture of rotamers (ratio 3:1); Rf 0.42 [CH2Cl2–EtOAc
(4:1)]; [a]D20 +29.1 (1.0, CHCl3); mmax(neat)/cm−1 3395, 2965, 1620;
dH(250 MHz, CDCl3) 7.42-7.25 (5H, m, ArH), 6.14-5.89 (1H, m,
CH=), 5.32-5.08 (2H, m, =CH2), 4.76 (0.75H, d, J 16.5, CH),
4.28 (0.75H, d, J 16.5, CH), 4.22-4.16 (0.75H, m, CH), 3.83
(0.25H, d, J 16, CH), 3.75-3.54 (1.75H, m, CH + minor rotamer
CH peaks), 3.39-3.23 (0.75H, m, CH), 3.22-3.08 (2H, m, CH2),
2.57-2.43 (0.75H, m, CH), 1.98-1.83 (0.25H, m, CH), 0.99 (0.8H,
d, J 6.5, CH3), 0.97 (2.2H, d, J 6.5, CH3), 0.93 (2.2H, d, J 6.5,
CH3), 0.90 (0.8H, d, J 6.5, CH3); dC(125 MHz, CDCl3) 173.5,
173.4, 139.5, 136.6, 132.1, 131.4, 129.0, 127.9, 127.6, 127.5, 126.8,
118.4, 118.0, 69.1, 66.3, 63.4, 61.6, 54.0, 44.3, 39.9, 39.4, 27.7,
26.1, 20.4, 20.1; HRMS (EI) found: M+, 261.1739, C16H23NO2
requires M+, 261.1729; LRMS m/z (EI) 260 (7%, M+), 230 (22),
162 (49), 150 (20), 91 (100).
Scheme 5 Asymmetric alkylation of the amide 5h. Reagents and condi-
tions: i, LDA, LiCl, THF, −78 ◦C, then MeI, 72%, dr 97:3.
To further illustrate the use of this chemistry, ring-closing
metathesis using Grubbs’ second generation catalyst13 with the
product 5m gave the novel 6-membered lactam 7 (Scheme 6).14
Reduction of the alkene gave the known compound 8, and this
completes a formal synthesis of the alkaloids (−)-coniine15 and
(+)-stenusine.16,17
N-Benzyl-N-[(S)-1-hydroxy-3-methylbutan-2-yl]-phenylaceta-
mide 5b. Using the general method, benzyl magnesium chloride
and the oxazolidinone 4a gave the amide 5b (0.16 g, 53%) as an
oil as a mixture of rotamers (ratio 3:1); Rf 0.38 [petrol–EtOAc
(3:2)]; [a]D20 +19.6 (1.0, CHCl3); mmax(neat)/cm−1 3370, 2960, 1620;
dH(250 MHz, CDCl3) 7.39-7.18 (10H, m, ArH), 5.25 (0.25H, d, J
15, CH), 4.77 (0.75H, d, J 16.5, CH), 4.37-4.22 (0.75H, m, CH),
4.22 (0.75H, d, J 16.5, CH), 3.92-3.53 (3.5H, m, 3 × CH + minor
rotamer CH peaks), 3.34-3.23 (0.25H, m, CH), 3.08 (0.75H, dt, J
10.5, 4, CH), 2.60-2.45 (0.75H, m, CH), 1.93-1.77 (0.25H, m, CH),
0.97 (0.8H, d, J 6.5, CH3), 0.91 (2.2H, d, J 6.5, CH3), 0.84 (2.2H, d,
J 6.5, CH3), 0.59 (0.8H, d, J 6.5, CH3); dC(125 MHz, CDCl3) 173.6,
139.5, 136.6, 135.4, 134.6, 129.2, 129.0, 128.9, 128.85, 128.75,
128.7, 127.9, 127.6, 127.4, 127.1, 126.9, 126.6, 69.2, 66.2, 63.5,
61.7, 54.3, 42.2, 41.7, 27.6, 26.1, 20.3, 20.0, 19.6; HRMS (EI)
found: M+, 311.1883, C20H25NO2 requires M+, 311.1885; LRMS
m/z (EI) 311 (9%, M+), 162 (37), 91 (100).
Scheme 6 Formal synthesis of (−)-coniine. Reagents and conditions: i,
CH2=CHCH2MgBr, THF, −78 ◦C, 60%; ii, Grubbs II, CH2Cl2, heat,
1.5 h, 94%; iii, H2, 5% Pd/C, MeOH, room temp., 87%.
Conclusions
The ring-opening of N-alkyl-oxazolidin-2-ones is possible using
Grignard reagents. A variety of substituted oxazolidin-2-ones
and different Grignard reagents can be used. In cases that give
low yields, some enhancement can be achieved by using excess
Grignard reagent or by conducting the reaction in the presence
N -p-Methoxybenzyl-N -[(S)-1-hydroxy-3-methylbutan-2-yl]-
but-3-enamide 5c. Using the general method, allyl magnesium
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bromide and the oxazolidinone 4b gave the amide 5c (0.2 g, 68%) as
an oil as a mixture of rotamers (ratio 2.3:1); Rf 0.2 [petrol–EtOAc
(3:2)]; [a]D20 19.6 (c 1.0, CHCl3); mmax(neat)/cm−1 3370, 2960, 1610;
dH(250 MHz, CDCl3) 7.32-6.80 (4H, m, ArH), 6.12-5.88 (1H, m,
CH=), 5.15-4.93 (2H, m, =CH2), 4.67 (1H, d, J 16.5, CH), 4.32
(1H, br t, J 5, OH), 4.20 (1H, d, J 16.5, CH), 3.79 (2.1H, s, CH3),
3.76 (0.9H, s, CH3), 3.71-3.65 (2H, m, CH2), 3.33-3.05 (3H, m,
CH and CH2), 2.56-2.38 (0.7H, m, CH), 1.93-1.80 (0.3H, m, CH),
0.99-0.85 (6H, m, 2 × CH3); dC(125 MHz, CDCl3) 173.4, 159.3,
158.8, 132.2, 131.5, 131.4, 129.0, 128.4, 128.2, 118.3, 117.9, 114.4,
114.3, 68.8, 66.3, 63.4, 61.5, 55.3, 55.2, 53.4, 39.9, 39.3, 27.8, 26.0,
20.3, 20.2, 20.1; HRMS (ES) found: MH+, 292.1918, C17H26NO3
requires MH+, 292.1913; LRMS m/z (ES) 314 (72%, MNa+), 292
(100, MH+).
222.1501, C13H19NO2 requires M+, 222.1494; LRMS m/z (ES) 244
(9%, MNa+), 222 (100, MH+).
N-[(S)-1-Hydroxy-3-phenylpropan-2-yl]-N-methyl-benzamide
5g. Using the general method, phenyl magnesium bromide and
the oxazolidinone 4c gave the amide 5g (0.17 g, 65%) as needles as a
mixture of rotamers (ratio 3:2); Rf 0.17 [petrol–EtOAc (2:3)]; m.p.
103–104 ◦C; [a]D −79.5 (0.4, CHCl3), lit.5 −75.4 (0.4, CHCl3),
20
no spectroscopic data reported; mmax(neat)/cm−1 3355, 1605, 1590;
dH(250 MHz, CDCl3) 7.35-6.84 (10H, m, ArH), 4.74-4.61 (0.6H,
m, CH), 4.11-3.56 (2.8H, m, CHCH2OH), 3.36-3.27 (0.6H, m,
CH), 3.15-2.60 (4.6H, m, CH2 and CH3), 1.80-1.68 (0.4H, m, CH);
dC(125 MHz, CDCl3) 173.6, 137.9, 137.3, 136.55, 136.5, 129.7,
129.1, 128.9, 128.8, 128.65, 128.6, 128.4, 128.0, 126.9, 126.7, 126.6,
63.1, 62.3, 62.0, 59.1, 35.1, 34.8, 34.2, 27.0; HRMS (ES) found:
MH+, 270.1488, C17H20NO2 requires MH+, 270.1494; LRMS m/z
(ES) 270 (100, MH+).
N-[(S)-1-Hydroxy-3-phenylpropan-2-yl]-N-methyl-but-3-ena-
mide 5d. Using the general method, allyl magnesium bromide
and the oxazolidinone 4c gave the amide 5d (0.23 g, 72%) as
an oil as a mixture of rotamers (ratio 3:1); Rf 0.15 [petrol–
N-p-Methoxybenzyl-N-[(S)-1-hydroxy-3-phenylpropan-2-yl]-
but-3-enamide 5h. Using the general method, allyl magnesium
bromide and the oxazolidinone 4d gave the amide 5h (0.28 g, 82%)
as an oil as a mixture of rotamers (ratio 4:1); Rf 0.21 [petrol–EtOAc
(3:2)]; [a]D20 29.5 (c 1.0, CHCl3); mmax(neat)/cm−1 3375, 2930, 1610;
dH(500 MHz, CDCl3) 7.31-7.09 (5.4H, m, ArH), 7.03 (1.6H, d, J
8.5, ArH), 6.84 (2H, d, J 8.5, ArH), 5.98-5.81 (1H, m, CH=), 5.19-
4.97 (2H, m, =CH2), 4.37 (1H, d, J 16, CH), 4.21-4.10 (1H, m,
CH), 3.82-3.47 (3H, m, CHCH2), 3.79 (2.4H, s, CH3), 3.77 (0.6H, s,
CH3), 3.16-3.01 (3.6H, m, 2 × CH2), 2.84-2.72 (0.4H, m, CH2);
dC(125 MHz, CDCl3, major rotamer) 173.2, 159.2, 138.7, 131.3,
129.2, 128.5, 128.2, 128.1, 126.5, 118.2, 114.3, 64.3, 63.9, 55.3,
52.7, 39.9, 34.3; HRMS (EI) found: M+, 339.1823, C21H25NO3
requires M+, 339.1834; LRMS m/z (ES) 362 (30%, MNa+), 340
(100, MH+).
20
EtOAc (3:7)]; [a]D −67.0 (1.1, CHCl3), −27.9 (10.7, CHCl3),
lit.19 −7.4 (10.7, CHCl3); HRMS (EI) found: M+, 233.1413,
C14H19NO2 requires M+, 233.1416. Spectroscopic data consistent
with literature.19
N-[(S)-1-Hydroxy-3-phenylpropan-2-yl]-N-methyl-acetamide
5e. Methyl magnesium bromide (0.5 mL, 1.5 mmol, 3 M in
Et2O) and magnesium bromide (0.28 g, 1.5 mmol) were added
to the oxazolidinone 4c (0.2 g, 1.0 mmol) in THF (5 mL) at
−78 ◦C. The mixture was allowed to warm to room temperature
over 16 h. Aqueous NH4Cl (5 mL) was added and the mixture was
extracted with Et2O (3 × 20 mL), dried (Na2SO4) and evaporated.
Purification by column chromatography on silica, eluting with
petrol–EtOAc (1:3), gave the amide 5e (0.08 g, 39%) as an oil as a
20
N-[(R)-2-Hydroxy-1-phenylethyl]-N-methyl-but-3-enamide 5i.
Using the general method, allyl magnesium bromide and the
oxazolidinone 4e gave the amide 5i (0.21 g, 86%) as needles as
a mixture of rotamers (ratio 3:1); Rf 0.29 [petrol–EtOAc (3:7)];
mixture of rotamers (ratio 2:1); Rf 0.04 [petrol–EtOAc (1:3)]; [a]D
−50.0 (1.0, CHCl3), lit.5 −36.0 (3.9, CHCl3), no spectroscopic data
reported; mmax(neat)/cm−1 3355, 2925, 1615; dH(250 MHz, CDCl3)
7.32-7.11 (5H, m, ArH), 4.54-4.43 (0.7H, m, CH), 4.16-4.01 (0.3H,
m, CH), 3.82-3.65 (2H, m, CH2), 2.96-2.66 (5H, m, CH2 and CH3),
2.03 (2H, s, CH3), 1.79 (1H, m, CH3); dC(125 MHz, CDCl3) 172.4,
172.2, 138.0, 137.6, 128.7, 128.7, 128.7, 128.4, 126.7, 126.4, 62.9,
62.3, 62.2, 58.8, 35.1, 34.4, 33.1, 26.5, 22.4, 21.4; HRMS (ES)
found: MNa+, 230.1151, C12H17NO2Na requires MNa+, 230.1157;
LRMS m/z (ES) 230 (5%, MNa+), 208 (100, MH+).
m.p. 37–38 ◦C; [a]D −118.0 (1.4, CHCl3); mmax(neat)/cm−1 3405,
20
1615; dH(250 MHz, CDCl3) 7.40-7.20 (5H, m, ArH), 6.13-5.92
(1H, m, CH=), 5.85 (1H, dd, J 9.5, 5, CH), 5.23-5.12 (2H, m,
=CH2), 4.22-4.02 (2H, m, CH2), 3.37 (0.5H, br d, J 7, CH2), 3.23
(1.5H, dt, J 7, 1.5, CH2), 2.77 (3H, s, CH3), 2.55 (1H, br s, OH);
dC(62 MHz, CDCl3) 172.9, 172.8, 137.1, 136.7, 131.9, 131.1, 128.9,
128.7, 127.9, 127.7, 127.7, 126.9, 118.0, 61.6, 61.4, 61.3, 58.1, 39.4,
39.0, 31.0, 28.3; HRMS (ES) found: MH+, 220.1327, C13H18NO2
requires MH+, 220.1338; LRMS m/z (ES) 242 (18%, MNa+), 220
(100, MH+); Anal. calcd for C13H17NO2: C, 71.21; H, 7.81; N, 6.39.
Found: 71.15; H, 7.88; N, 6.20%.
N-[(S)-1-Hydroxy-3-phenylpropan-2-yl]-N-methyl-propiona-
mide 5f. In the same way as the amide 5e, ethyl magnesium
bromide (2.6 mL, 2 mmol, 0.8 M in THF), magnesium bromide
(0.19 g, 1 mmol) and the oxazolidinone 4c (0.2 g, 1.0 mmol) gave,
after purification by column chromatography on silica, eluting
with CH2Cl2–Et2O (7:3), the amide 5f (0.1 g, 44%) as an oil
as a mixture of rotamers (ratio 2.6:1); Rf 0.22 [CH2Cl2–Et2O
N-[(R)-2-Hydroxy-1-phenylethyl]-N-methyl-2-phenylacetamide
5j. Using the general method, benzyl magnesium chloride
and the oxazolidinone 4e gave the amide 5j (0.19 g, 70%) as
(7:3)]; [a]D −28.0 (1.1, CHCl3); mmax(neat)/cm−1 3375, 2940, 1615;
20
needles as a mixture of rotamers (ratio 2.5:1); Rf 0.22 [petrol–
dH(250 MHz, CDCl3) 7.31-7.11 (5H, m, ArH), 4.54-4.43 (0.7H,
m, CH), 4.18-4.06 (0.3H, m, CH), 3.81-3.65 (2H, m, CH2), 3.17-
3.08 (0.7H, m, OH), 2.94-2.70 (5.3H, m, OH, CH2 and CH3),
2.26 (2H, q, J 7.5, CH2), 1.07 (2.1H, t, J 7.5, CH3), 0.92 (0.9H,
t, J 7.5, CH3); dC(100 MHz, CDCl3) 176.2, 175.6, 138.6, 138.0,
129.3, 129.25, 129.2, 128.9, 127.2, 126.9, 63.9, 62.8, 61.2, 60.5,
35.8, 34.8, 33.5, 27.9, 27.1, 26.6, 9.8, 9.6; HRMS (ES) found: M+,
◦
EtOAc (2:3)]; m.p. 73–74 C, lit.18 75–77 ◦C; [a]D −113.0 (1.1,
20
CHCl3), lit.20 −117 (1.25, CHCl3); HRMS (ES) found: MH+,
270.1496, C17H20NO2 requires MH+, 270.1494. Spectroscopic
data consistent with literature.20
N-[(R)-2-Hydroxy-1-phenylethyl]-N-methyl-propionamide 5k.
In the same way as the amide 5e, ethyl magnesium bromide
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(1:1)]; [a]D −25.2 (c 1.0, CHCl3); mmax(neat)/cm−1 3400, 2940,
1610; dH(400 MHz, CDCl3) 7.21-7.11 (5H, m, ArH), 7.03 (2H, d,
J 10, ArH), 6.88 (2H, d, J 10, ArH), 5.96-5.89 (1H, m, CH=),
5.11-4.91 (2H, m, =CH2), 4.54-4.30 (2H, m, CH2), 3.82 (3H, s,
CH3), 3.77 (2H, d, J 7, CH2), 3.73-3.68 (1H, m, CH), 3.34-3.29
(1H, m, CH), 3.41-3.06 (2H, m, CH2), 1.73 (1H, br s, OH), 1.28
(0.4H, s, CH3), 1.21 (2.6H, s, CH3); dC(100 MHz, CDCl3) 176.1,
159.4, 138.6, 138.4, 138.1, 129.3, 129.2, 129.0, 128.7, 128.5, 128.4,
128.0, 127.7, 126.8, 126.4, 115.8, 115.6, 115.1, 114.3, 114.2, 64.4,
63.9, 63.2, 62.5, 55.2, 52.0, 51.2, 42.1, 34.2, 18.7; HRMS (ES)
found: MH+, 354.2064, C22H28NO3 requires MH+, 354.2069;
LRMS m/z (ES) 376 (10%, MNa+), 354 (100, MH+); Anal. calcd
for C22H27NO3: C, 74.76; H, 7.70; N, 3.96. Found: 74.71; H,
7.61; N, 3.99%. The diastereomer ratio was determined by HPLC
using an Alltech Alltima ODS 3 lm column, length 150 mm, i.d.
4.6 mm, MeCN–H2O 40:60, flow rate 1 mL per min, detection at
254 nm, retention times: 17.5 min (minor) and 18.7 min (major).
20
(2.6 mL, 2 mmol, 0.8 M in THF), magnesium bromide (0.19 g,
1 mmol) and the oxazolidinone 4e (0.2 g, 1.0 mmol) gave, after
purification by column chromatography on silica, eluting with
CH2Cl2–Et2O (7:3), the amide 5k (0.06 g, 30%) as an oil as a
mixture of rotamers (ratio 2.4:1); Rf 0.27 [EtOAc–MeOH (98:2)];
[a]D −45.9 (1.1, CHCl3); mmax(neat)/cm−1 3385, 2935, 1615;
20
dH(250 MHz, CDCl3) 7.34-7.14 (5H, m, ArH), 5.85 (0.7H, dd,
J 9, 5, CH), 5.10 (0.3H, dd, J 9, 4, CH), 4.15-3.94 (2H, m, CH2),
3.54 (1H, br s, OH), 2.72 (2.1H, s, CH3), 2.70 (0.9H, s, CH3),
2.42 (2H, q, J 7.5, CH2), 1.13 (2.1H, t, J 7.5, CH3), 1.11 (0.9H,
t, J 7.5, CH3); dC(125 MHz, CDCl3) 175.7, 175.5, 137.3, 137.0,
128.6, 128.4, 127.8, 127.7, 127.6, 126.8, 61.6, 61.4, 61.3, 58.1, 30.7,
28.1, 27.3, 26.7, 9.6, 9.2; HRMS (ES) found: MNa+, 230.1152,
C12H17NO2Na requires MNa+, 230.1157; LRMS m/z (ES) 230
(47%, MNa+), 208 (100, MH+).
N-[(R)-2-Hydroxy-1-phenylethyl]-N-methyl-2-heptanamide 5l.
Using the general method, hexyl magnesium bromide and the
oxazolidinone 4e gave the amide 5l (0.14 g, 52%) as an oil
as a mixture of rotamers (ratio 3:1); Rf 0.27 [petrol–EtOAc
1,6-Dihydro-1-[(R)-2-hydroxy-1-phenylethyl]pyridine-2(3H)-
one 7. Grubbs second generation catalyst (C48H65Cl2N2PRu)
(137 mg, 0.16 mmol) was added in two portions to the amide
5m (1.0 g, 4.07 mmol) in CH2Cl2 (30 mL) at 40 ◦C. After 1.5 h, the
mixture was cooled to room temp. After 1 h DMSO (0.5 mL) was
added. After 2 h, the solvent was evaporated and the residue was
purified by column chromatography on silica, eluting with petrol–
EtOAc (1:9), gave the lactam 7 (833 mg, 94%) as an oil; Rf 0.30
(1:1)]; [a]D −95.3 (1.1, CHCl3); mmax(neat)/cm−1 3385, 2925, 1620;
20
dH(250 MHz, CDCl3) 7.37-7.18 (5H, m, ArH), 5.86 (0.75H, dd, J
9.5, 5, CH), 5.15 (0.25H, dd, J 9.5, 5, CH), 4.15-4.07 (2H, m, CH2),
2.76 (3H, s, CH3), 2.39 (2H, t, J 7.5, CH2), 1.71-1.62 (2H, m, CH2),
1.39-1.26 (6H, m, 3 × CH2), 0.91-0.86 (3H, m, CH3); dC(125 MHz,
CDCl3) 175.4, 174.9, 137.2, 137.0, 128.9, 128.7, 127.9, 127.8, 126.8,
61.9, 61.6, 61.3, 58.3, 34.2, 33.7, 31.6, 31.2, 29.2, 29.1, 28.1, 25.5,
25.1, 22.6, 14.1; HRMS (ES) found: MH+, 264.1959, C16H26NO2
requires MH+, 264.1964; LRMS m/z (ES) 550 (100%, M2HNa+),
286 (18, MNa+), 264 (50, MH+).
[petrol–EtOAc (1:9)]; [a]D −65.8 (c 0.8, CHCl3); mmax(neat)/cm−1
20
3350, 2880, 1615; dH(500 MHz, CDCl3) 7.35-7.26 (5H, m, ArH),
=
5.89-5.86 (1H, m, CH), 5.76-5.62 (2H, m, CH CH), 4.19-4.12
(2H, m, CH2), 3.90-3.52 (2H, m, CH2), 3.07-3.04 (2H, m, CH2),
2.16 (1H, br s, OH); dC(125 MHz, CDCl3) 169.1, 136.4, 127.9,
127.8, 122.0, 121.0, 61.4, 58.5, 44.6, 32.7; HRMS (ES) found:
MNa+, 240.0992, C13H15NO2Na requires MNa+, 240.1000; LRMS
m/z (ES) 457 (100%, M2Na+), 240 (82, MNa+), 218 (22, MH+).
N-Allyl-N-[(R)-2-Hydroxy-1-phenylethyl]-but-3-enamide 5m.
Using the general method, allyl magnesium bromide (7 mmol),
and the oxazolidinone 4f (0.2 g, 1.0 mmol) gave, after purification
by column chromatography on silica, eluting with petrol–EtOAc
(3:2), the amide 5m (0.15 g, 60%) as an oil; Rf 0.21 [petrol–EtOAc
(R)-1-(2-Hydroxy-1-phenylethyl)piperidin-2-one 8. The lactam
7 (1.0 g, 4.6 mmol) and palladium on charcoal (100 mg, 5%) in
MeOH (20 mL) were stirred under an atmosphere of hydrogen at
room temp. After 48 h, the mixture was filtered, the solvent was
evaporated and the residue was purified by column chromatog-
raphy on silica, eluting with CH2Cl2–MeOH (95:5), to give the
lactam 8 (0.88 g, 87%) as needles; Rf 0.50 [CH2Cl2–MeOH (95:5)];
20
(3:2)]; [a]D −51.0 (1.0, CHCl3); mmax(neat)/cm−1 3395, 2930,
1615; dH(250 MHz, CDCl3) 7.37-7.19 (5H, m, ArH), 6.09-5.91
(1H, m, CH=), 5.73-5.58 (1H, m, CH=), 5.54 (1H, t, J 6.5,
NCH), 5.22-5.07 (4H, m, 2 × =CH2), 4.12 (2H, br d, J 6.5, CH2),
3.84-3.65 (2H, m, CH2), 3.21 (2H, br d, J 6.5, CH2); dC(125 MHz,
CDCl3) 173.4, 137.1, 135.0, 134.1, 131.8, 131.6, 129.0, 128.7,
128.5, 128.5, 128.1, 127.9, 127.0, 118.0, 116.9, 63.1, 62.3, 62.1,
62.0, 60.9, 48.2, 45.4, 39.3; HRMS (EI) found: M+, 245.1413,
C15H19NO2 requires M+, 245.1416; LRMS m/z (EI) 245 (6%, M+),
214 (33), 146 (51), 101 (35), 86 (100).
◦
◦
m.p. 112–114 C, lit.16 113–115 C; [a]D −79.8 (c 0.5, CHCl3), lit.16
−80 (0.5, CH2Cl2); Anal. calcd for C13H17NO2: C, 71.21; H, 7.81;
N, 6.39. Found: 71.16; H, 7.78; N, 6.43%. NMR spectroscopic
data as reported.16
20
N-[(S)-1-Hydroxy-3-phenylpropan-2-yl]-N-p-methoxybenzyl-2-
methylbut-3-enamide 6. n-Butyllithium (2.5 mL, 6 mmol, 2.5 M)
was added to diisopropylamine (0.9 mL, 6.6 mmol) in THF
(10 mL) at −78 ◦C. The mixture was warmed to 0 ◦C then
re-cooled to −78 ◦C and the amide 5h (1.0 g, 2.9 mmol) in THF
(10 mL) was added. After 1 h, LiCl (0.75 g, 17.4 mmol) was added.
After 30 min, iodomethane (0.36 mL, 17.4 mmol) was added.
After 30 min, aqueous NH4Cl (10 mL) was added, the mixture was
warmed to room temperature and was extracted with EtOAc (3 ×
20 mL), dried (Na2SO4) and evaporated. Purification by column
chromatography on silica, eluting with petrol–EtOAc (1:1), gave
the amide 6 (0.74 g, 72%) as an oil as a mixture of diastereomers (dr
97:3) and a mixture of rotamers (ratio 7:1); Rf 0.55 [petrol–EtOAc
Acknowledgements
We would like to thank the EPSRC (GR/T18240/01) and
AstraZeneca for funding. We acknowledge support from the
University of Sheffield and from the ERASMUS scheme.
Notes and references
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1414 | Org. Biomol. Chem., 2008, 6, 1410–1415
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3 For some examples of hydroxide-promoted opening of oxazolidin-2-
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This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 1410–1415 | 1415
©