Ring Opening Reactions of N-Alkyl Oxazolidinones with Organolithium Reagents

Article abstract of DOI:10.1055/s-2003-44972

Addition of primary, secondary and aryl organolithium reagents to N-methyl and N-benzyl oxazolidin-2-ones give N-acyl amino alcohols in 30-93% yields. Application to the synthesis of an imidazoyl oxazoline is demonstrated.

Full text of DOI:10.1055/s-2003-44972

338
LETTER
Ring Opening Reactions of N-Alkyl Oxazolidinones with Organolithium
Reagents
R
ingOpening
i
Reacti
m
ons of
N
-Alkyl
O
xa
o
z
olidinones n Jones,*1 Helen C. Norton1
School of Natural Sciences – Chemistry, University of Newcastle upon Tyne, Bedson Building, Newcastle upon Tyne NE1 7RU, UK
Fax +44(114)2229346; E-mail: simon.jones@sheffield.ac.uk.
Received 5 September 2003
The key starting materials for this work were N-methyl
Abstract: Addition of primary, secondary and aryl organolithium
and N-benzyl oxazolidin-2-ones. These have been report-
ed as a by-product in Evans type asymmetric alkylation
reagents to N-methyl and N-benzyl oxazolidin-2-ones give N-acyl
amino alcohols in 30–93% yields. Application to the synthesis of an
reactions and little mention has been made of their reac-
tivity.3 As representative examples, we chose two N-me-
thyl and one N-benzyl oxazolidin-2-ones which were
easily prepared by deprotonation of the oxazolidin-2-one
and alkylation with methyl iodide or benzyl bromide, re-
spectively. The reactions were found to be slow, requiring
3 equivalents of alkyl halide, but excellent yields were
achieved for the (S)-valine and (S)-phenylalanine derived
oxazolidinones (Scheme 1, Table 1). These materials
were obtained essentially pure as determined by 1H NMR
spectroscopy, and were used in crude form throughout.4
imidazoyl oxazoline is demonstrated.
Key words: acylations, amides, amino alcohols, organometallic
reagents, rearrangements
Growing interest in asymmetric synthesis has increased
the need for methodology, which facilitates the easy in-
stallation of a stereogenic centre within a molecule. Ana-
logues of amino acids and amino alcohols fulfil this role
acting as key chiral building blocks and their applicability
is self-evident given their presence in a wide range of syn-
thetic and natural products such as those in in sphingolip-
ids and the side chain of taxol. Chiral amino alcohols also
form the basis of many stereodirecting groups in auxilia-
ries and catalysts,2 an elegant example being the use of
pseudoepedrine in Myers’ auxiliary for asymmetric alkyl-
ation (Figure 1).2a
O
O
i. n-BuLi,
THF, –78 °C
R2
N
O
HN
R1
O
ii. R2-X, 0 °C
X = Br, I
R1
R1 = i-Pr, Bn
R2 = Me, Bn
CH3
O
Scheme 1
N
OH CH3
Table 1 Yields of N-Alkyl Oxazolidin-2-ones
Figure 1
Entry
R1
R2
Yield (%)a
[a]D25 (c 1, CHCl3)
+40.8
1
2
3
i-Pr
Bn
Me
Me
Bn
96
94
97
However, the restricted availability of certain amino alco-
hols, especially for those classed as regulated chemicals
means that some methodologies, like those detailed
above, are not available in certain regions of the world.
+65.1
i-Pr
–17.0
Additionally, classical synthesis of N-acyl amino alcohols a Refers to crude yield.
via condensation of an amino alcohol with an acid chlo-
ride is not always trivial, especially when the acid chloride
Addition reactions were carried out at –78 ºC in THF over
2 hours (Scheme 2, Table 2).5 It was found that organo-
lithium reagents were essential in all of these reactions
and that use of Grignard reagents led to recovered starting
material. In all cases compounds were isolated using
column chromatography that somewhat reduced the
yield due to the polar nature of the functional groups and
in most cases, these products existed as a mixture of
rotamers, which is consistent with previous observations
on similar classes of compounds.6 Products were isolated
in varied yields, with the addition of n-BuLi providing the
most promising result (entries 2 and 9). In the case of
addition of MeLi (Entry 1) the low yield was attributed to
is difficult to generate or unstable. In the process of devel-
oping methodology aimed towards a new approach to the
synthesis of oxazolines, we discovered that N-alkyl N-
acyl amino alcohols could be easily generated from the
corresponding N-alkyl oxazolidin-2-ones. Herein we de-
scribe our preliminary findings of this work.
SYNLETT 2004, No. 2, pp 0338–0340
0
2.
0
2.
2
0
0
4
Advanced online publication: 08.12.2003
DOI: 10.1055/s-2003-44972; Art ID: D22503ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Ring Opening Reactions of N-Alkyl Oxazolidinones
339
increased water solubility of this product, since a higher although a more accurate determination was not possible
yield was obtained for the N-benzyl analogue (entry 8). It due to overlapping signals from the individual rotamers of
1
is important to note that the formation of the amide de- each diastereoisomer in the H NMR spectra. Although,
rived from N-methyl imidazole (entries 5 and 12) by clas- separation of the individual diastereoisomers was not pos-
sical methods was not possible due to decomposition sible in these cases, this methodology offers potential for
during the preparation of the imidazole acid chloride.
a new approach to the synthesis of enantiomerically en-
riched a-substituted carboxylate derivatives. This method
is particularly attractive since the organolithium reagent
rapidly racemises, essentially leading to dynamic kinetic
resolution.
R1
O
O
R2
R3-Li, THF
–78 °C, 2 h
R3
N
O
N
R2
OH
The second reaction of note involved ring opening with
2,3-dihydro-5-furyllithium7 (entry 15) in an attempt to
further demonstrate the use of this methodology in the
synthesis of amides that would be otherwise difficult to
prepare.
R1
Scheme 2
Both t-BuLi (entries 3 and 10) and 9-lithioanthracene
(entries 6 and 13) were essentially unreactive under the
conditions described presumably due to their large steric
bulk.
This reaction proceeded well, giving good mass return of
the desired ring opened product 1 (Scheme 3). However,
the crude reaction product underwent rapid rearrangement
on silica gel to a diastereomeric mixture of spiroacetals 2
and 3 (dr, 4:1). The assignment of the major diastereoiso-
mer is arbitrary at this time since the absolute configura-
tion of each spiroacetal has not been determined. The ring
Of interest, reaction of s-BuLi with either oxazolidin-2-
one (entries 7 and 14) gave rise to products with a low, but
measurable diastereomeric excess. The diastereomeric
ratio in each case was estimated to be approximately 3:2,
Table 2 Ring Opening Reaction of Oxazolidin-2-ones with Organolithium Reagents
25
Entry
1
R1
R2
R3
Yield (%)a
Rotameric ratio
1.7:1
1.7:1
NA
[a]D
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Bn
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bn
Me
30d
93
0
–44.8 (c 1, CHCl3)
–23.1 (c 2.5, CHCl3)
NA
2
n-Bu
t-Bu
Ph
3
4
49
35
0
1.2:1
16:1
–24.8 (c 2.6, CHCl3)
–46.9 (c 1.4, CHCl3)
NA
5
NMIb
ANTc
s-Bu
Me
6
NA
7
60
70d
82
0
2.1:1
1.4:1
2.5:1
NA
–25.3 (c 0.9, CHCl3)
–36.0 (c 3.9, CHCl3)
+3.6 (c 2.7, CHCl3)
NA
8
9
Bn
n-Bu
t-Bu
Ph
10
11
12
13
14
15
16
Bn
Bn
39
59
0
1.1:1
NAe
–75.4 (c 0.4, CHCl3)
–31.8 (c 0.3, CHCl3)
NA
Bn
NMIb
ANTc
s-Bu
VFf
Bn
NA
Bn
58
51g
70
2.5:1
NAe
–41.2 (c 2.0, CHCl3)
Not determined
–12.0 (c 1.0, CHCl3)
i-Pr
i-Pr
NMI
NAe
a Refers to isolated yield.
b 2-N-Methyl imidazole.
c 9-Anthryl.
d 2 equiv of MeLi used.
e Only 1 rotamer was observed.
f 2,3-Dihydro-5-furyl.
g Isolated yield of spiroacetals 2 and 3.
Synlett 2004, No. 2, 338–340 © Thieme Stuttgart · New York

340
S. Jones, H. C. Norton
LETTER
Acknowledgement
O
O
Me
We thank the EPSRC for funding (HCN).
i.
Li
O
N
O
N
THF, –78 °C
O
Me
OH
References
1
ii. Silica gel
O Me
(1) Current address: Department of Chemistry, University of
Sheffield, Dainton Building, Brook Hill, Sheffield S3 7HF,
UK.
O
Me
N
(2) (a) Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J. L. J.
Am. Chem. Soc. 1994, 116, 9361. (b) Micouin, L.; Schanen,
V.; Riche, C.; Chiaroni, A.; Quirion, J.-C.; Husson, H.-P.
Tetrahedron Lett. 1994, 35, 7223. (c) Myers, A. G.;
Gleason, J. L.; Yoon, T. J. Am. Chem. Soc. 1995, 117, 8488.
(d) Myers, A. G.; Yoon, T. Tetrahedron Lett. 1995, 36,
9429. (e) Micouin, L.; Jullian, V.; Quirion, J.-C.; Husson,
H.-P. Tetrahedron: Asymmetry 1996, 7, 2839.
N
O
O
O
O
2
3
Scheme 3
(3) Bull S. D., Davies S. G., Jones S., Sanganee H. J.; J. Chem.
Soc., Perkin Trans. 1; 1999, 387.
(4) Analytical samples were prepared by column
chromatography and/or recrystallisation. All new
compounds reported had satisfactory analytical data that will
be reported in full in due course.
(5) Typical Experimental Procedure: n-BuLi (1.6 M, 0.44
mL, 0.70 mmol) was added to a solution of N-methyl 4(S)-
iso-propyl oxazolidin-2-one (0.1 g, 0.70 mmol) at –78 °C.
The reaction was warmed to 0 °C and after 2 h quenched
with H2O (2 mL) and extracted with EtOAc (5 × 10 mL). The
organic extracts were combined and washed with NH4Cl (5
mL), dried over NaSO4 and the solvent removed under
vacuum to give a pale yellow oil as the crude product
(0.157 g) which was purified using flash column
opening reaction was repeated and spiroacetal formation
confirmed by treatment of the crude reaction product 1
with a catalytic quantity of TFA in CH2Cl2 giving an iden-
tical mixture of the spiroacetals 2 and 3 in 68% isolated
yield. Separation of each of these diastereomeric com-
pounds was not possible at this time.
In order to demonstrate the use of this methodology in the
synthesis of an otherwise problematic target, the oxazoli-
nyl imidazole 4 was prepared (Scheme 4). The N-benzyl
oxazolidinone 5 was ring opened, followed by hydro-
genolysis giving the hydroxy-amide 6 in near quantitative
yield. Final cyclisation using diethylamino sulfurtri-
fluoride (DAST)8 proved to the be the more problematic
step only affording the desired oxazoline 4 in 20% isolat-
ed yield. Although the yield in the last step was poor, the
synthesis of hydroxy amide 6 by more classical methods
(e.g. DCC coupling, acid chloride formation) proved
problematic and never gave the desired product. The route
described provides an effective route to this compound.
chromatography (EtOAc) to give a clear oil (0.131 g, 93%);
[a]D25 –23.1 (c 2.5, CHCl3); ratio of rotamers A/B = 1.7:1.
Rotamer A: 1H NMR (500 MHz, CDCl3): d = 0.80 (d, J = 6.4
Hz, 3 H, CH3CH), 0.86 (t, J = 7.3 Hz, 3 H, CH3CH2), 0.93
(d, J = 6.4 Hz, 3 H, CH3CH), 1.29 (m, 2 H, CH3CH2), 1.55
(m, 2 H, CH3CH2CH2), 1.84 [m, 1 H, (CH3)2CH], 2.33 (m, 2
H, CH3CH2CH2CH2), 2.84 (s, 3 H, NCH3), 3.24 (s, br d, 1 H,
OH), 3.97–3.42 (range of multiplets, 3 H, HOCH2CH). 13
NMR (125 MHz, CDCl3): d = 22.7 (CH3CH), 27.6
C
Me
[(CH3)CH2CH2], 27.7 [(CH3)2CH], 34.1 [CH3(CH2)2CH2],
61.9 (HOCH2), 65.6 (HOCH2CH), 175.4 [C(O)N]. Rotamer
B: 1H NMR (500 MHz, CDCl3): d = 0.77 (d, J = 6.7 Hz, 3 H,
CH3CH), 0.85(t, J = 7.3 Hz, 3 H, CH3CH2), 0.91(d, J = 6.4
Hz, 3 H, CH3CH), 1.68 [m, 1 H, (CH3)2CH], 2.28 (m, 2 H,
CH3CH2CH2CH2), 2.68 (s, 3 H, NCH3), 3.24 (s, br d, 1 H,
N
O
O
Li
N
Bn
i.
N
N
O
N
THF, –78 °C
70%
N
Bn
OH
OH), 3.97–3.42 (range of multiplets, 3 H, HOCH2CH). 13
NMR (125 MHz, CDCl3): d = 14.0 (CH3CH), 26.8
[(CH3)2CH], 27.3 (CH3CH2CH2), 32.1 (N-CH3), 33.4
C
Me
ii. H2, Pd/C
AcOH
5
> 95%
[CH3(CH2)2CH2], 60.8 (HOCH2), 63.3 (HOCH2CH), 175.1
[C(O)N]. MS (EI): m/z calcd [M+] for C11H23NO2: 201.1729;
O
+
iii. DAST
O
N
found: 201.1719. MS (EI): m/z (%) = 201 (1) [C11H23NO2 ],
N
N
N
N
183 (2), 170 (1) [C10H20N+], 86 (100), 74 (44).
(6) Jullian, V.; Quirion, J.-C.; Husson, H.-P. Synthesis 1997,
1091.
N
CH2Cl2
20%
H
OH
Me
Me
(7) Jarowicki, K.; Kocienski, P. J.; Qun, L. Org. Synth. 2002, 79,
11.
6
4
(8) Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D.
R. Org. Lett. 2000, 2, 1165.
Scheme 4
In conclusion an alternative synthesis of N-acyl-N-alkyl
amino alcohols has been described which utilises N-alkyl
oxazolidin-2-ones and a range of organolithium reagents.
This methodology should overcome circumstances where
the direct use of regulated amino alcohols is prohibited.
Synlett 2004, No. 2, 338–340 © Thieme Stuttgart · New York