Copper Catalyzed Assembly of N-Aryloxazolidinones: Synthesis of Linezolid, Tedizolid, and Rivaroxaban

Article abstract of DOI:10.1002/ejoc.201600033

The total synthesis of oxazolidinone-based pharmaceuticals, linezolid, tedizolid and rivaroxaban is reported. They are synthesized using a recently reported copper-catalyzed one-pot cyclization and arylation as the key step to construct the N-aryloxazolidinone core. Active pharmaceutical ingredients (API) were synthesized from a common synthetic pool of a simple protected amino alcohol in 22 %, 61 % and 40 % total synthesis yields, respectively.

Full text of DOI:10.1002/ejoc.201600033

DOI: 10.1002/ejoc.201600033
Full Paper
Homogeneous Catalysis
Copper Catalyzed Assembly of N-Aryloxazolidinones: Synthesis
of Linezolid, Tedizolid, and Rivaroxaban
William Mahy,[a] Jamie A. Leitch,[b] and Christopher G. Frost*[a,b]
Abstract: The total synthesis of oxazolidinone-based pharma- the N-aryloxazolidinone core. Active pharmaceutical ingredients
ceuticals, linezolid, tedizolid and rivaroxaban is reported. They (API) were synthesized from a common synthetic pool of a sim-
are synthesized using a recently reported copper-catalyzed ple protected amino alcohol in 22 %, 61 % and 40 % total syn-
one-pot cyclization and arylation as the key step to construct thesis yields, respectively.
Introduction
Over recent decades, the synthesis and modification of the N-
aryloxazolidinone motif has received great attention due its
prevalence in a variety of modern pharmaceuticals.[1] DuPont
found that these structures possess potent activity as antibacte-
rial agents through a unique mechanism of action. This family
of antibiotics function by selectively inhibiting protein synthesis
in bacteria cells. Linezolid, the first of these pharmaceuticals,
was approved by the FDA in 2000 to treat severe Gram-positive
bacterial infections such as MRSA and VRE.[2] Due to its unique
mechanism of action little cross resistance was found with other
common antibacterials. Despite this, resistance against linezolid
itself has been found, and the second generation analogue, te-
dizolid, has been shown to have wide spread potency against
linezolid-resistant gram positive bacteria.[3] Rivaroxaban is the
first available orally active direct factor Xa inhibitor and is used
Figure 1. Oxazolidinone-based API's synthesized in this study.
post-surgery to prevent blood clots and in cases of people suf-
fering from non-valvular atrial fibrillation.[4] The chemical struc-
ture of these three drug compounds can be seen to possess a
similar common core, making up of three rings (Figure 1); (A) a
shown to permit access to a wide range of highly decorated
pharmaceutically relevant oxazolidinone motifs. This transfor-
5-substituted oxazolidinone ring, (B) 1,4-substituted aryl ring
where a small group meta to the nitrogen is also predominant
mation was also shown to possess a vast functional group toler-
and (C) the most structurally diverse ring, allowing for varied
ance with a wide range of reactive functionality for further deri-
analogues.
vation. This report describes the application of these initial
studies in the total syntheses of linezolid, tedizolid and rivaroxa-
We have previously reported a copper-catalyzed one-pot cy-
clization and arylation used in synthesis of the N-aryloxazol-
ban. The racemates of these drugs were synthesized as a proof
idinone motif (Scheme 1).[5] This reaction methodology was ap-
of concept.
plied to the synthesis of the reversible and selective monoam-
Retrosynthetic analysis of the common core could envisage
ine oxidase (MAO) inhibitor, Toloxatone, which has been used
in the treatment of depression.[6] This reaction protocol was
going back to one universal starting material for each of the
drugs, 3-amino-1,2-propanediol (Scheme 2). From this, the for-
ward route would begin with the construction of the N-ethyl
carbamate protected structure primed for the key copper-cata-
lyzed one-pot cyclization and arylation step. This step would
introduce the (A) and (B) rings. Following this, cross coupling
could be used to install the (C) ring. Subsequent late stage
FGI('s) would be used to leave the desired functionality in the
5-position of the (A) ring to give the fully furnished drug mol-
ecules.
[a] Centre for Sustainable Chemical Technologies, University of Bath,
Bath, BA2, 7AY, United Kingdom
http://www.bath.ac.uk/chemistry/contacts/academics/chris_frost/
[b] Department of Chemistry, University of Bath,
Bath, BA2 7AY, United Kingdom
E-mail: c.g.frost@bath.ac.uk
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600033.
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para-substituted halogen is also necessary to allow addition of
(C) ring via cross coupling methodology.
The copper-catalyzed cyclization and arylation protocol was
initially tested. However this only gave conversion to product
in poor yields. From this, further investigation was needed in
attempt to determine more bespoke conditions for this trans-
formation. Low yields were deduced to be due to potential sa-
ponification of the oxazolidinone product and subsequent po-
tential N-/O-arylations. Varying the quantity of aryl iodide, tem-
perature and the presence of any additives were tested under
the reaction conditions (Table 1). tBuOH and HFIP were added
in order to attempt to suppress saponification. Unfortunately
the isolated yields for any of these variations remained uni-
formly poor. As such, it was proposed that this was a non-viable
route towards the high value linezolid and tedizolid intermedi-
ate.
Table 1. Optimisation copper-catalyzed one-pot cyclization and arylation syn-
thesising pharmaceutical intermediate; L1 = 2,2,6,6-tetramethyl-3,5-heptane-
dione.
Scheme 1. Copper-catalyzed construction of the N-aryloxazolidinone core
and the application to the total synthesis of Toloxatone.
Entry
Ar–I (equiv.)
T [°C]
Additive
4 [%][a]
1
2
3
4
5
6
1.0
1.4
1.8
1.8
1.8
1.8
80
80
80
100
80
80
–
–
–
–
34
33
44
35
28
0
Scheme 2. Retrosynthetic analysis of common core to universal amino alcohol
starting material.
tBuOH[b]
Results and Discussion
[b]
HFIP
The total synthesis of all three drugs was envisioned to stem
from a N,O-protected amino alcohol (Scheme 3) which is to be
used as a common synthetic pool for this work. This was ob-
tained by selective N-protection using ethyl chloroformate and
then a selective primary alcohol silyl protection governed by
protecting group choice.
[a] Isolated yield. [b] 1.5 equiv. hexafluoroisopropanol (HFIP).
On reflection of reactivity of these systems, it was then antic-
ipated that the same copper-catalyzed transformation could be
applied to 3-fluoroiodobenzene, followed by a selective iodin-
ation to give a similar intermediate. The introduction of iodide
functionality (cf. bromide) also allows access to further copper-
catalyzed systems for installation of the (C) ring. The reaction
of 3 with the fluorinated aromatic gave the corresponding N-
aryloxazolidinone cleanly in 91 % yield (Scheme 4).
Scheme 3. Synthesis of di-protected amino alcohol used as a synthetic pool
in pharmaceutical synthesis.
Scheme 4. Copper-catalyzed cyclization and arylation of meta-fluoroiodo-
benzene. L1 = 2,2,6,6-tetramethyl-3,5-heptanedione.
For the synthesis of linezolid and tedizolid it was of para-
mount importance install a di-halogenated aromatic motif. To
introduce the meta-fluoro substituent at this time was impor-
para-Selective electrophilic iodination using Wij's solution fa-
tant as late stage fluorinations could lead to selectivity issues cilitated the formation of the di-halogenated aromatic interme-
and waste of high value intermediates. The installation of a diate 6 in excellent yields (Scheme 5). This transformation also
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led to an unexpected protecting group exchange where only
the acetyl protected alcohol structure was observed. This struc-
ture served as the key common intermediate in the synthesis
of linezolid and tedizolid. The former will be discussed first.
Table 2. Transition metal-catalyzed amination of electron-rich aryl iodide.
Entry Cross coupling conditions[a]
Conv. [%][b]
1[5]
2[7]
3[8]
4[9]
5[9]
6[10]
CuI (10 %), L1 (20 %), Cs2CO3, MeCN, 80 °C, 20 h
CuI (10 %), L2 (10 %), K3PO4, 1,4-dioxane, 80 °C, 24 h
CuI (10 %), L3 (20 %), K2CO3, DMSO, 100 °C, 20 h
CuBr (20 %), L4 (20 %), K3PO4, DMF, 80 °C, 4 h
CuI (20 %), L4 (20 %), K3PO4, DMF, 60 °C, 20 h
0
9
30
78
30[c]
Pd(dba)2 (5 %), L5 (10 %), NaOtBu, PhMe, 100 °C, 20 h 10[c,d]
Scheme 5. para-Selective aromatic iodination and protecting group ex-
change.
[a] L1 = 2,2,6,6-tetramethyl-3,5-heptanedione, L2 = ethylenediamine, L3 =
proline, L4 = rac-BINOL, L5 = Xantphos. [b] 1H NM conversion. [c] Modifica-
tion of literature procedure. [d] Protodehalogenation observed.
Hydrolysis of the acetyl structure under basic conditions in
methanolic dichloromethane gave clean access to the free alco-
hol structure (Scheme 6, a). Subsequent nosylation gave the
activated alcohol primed for nucleophilic substitution in excel-
lent yields. Aqueous ammonium hydroxide was used to gener-
ate the primary amine. This was telescoped through to acetyl-
ation in a modest yield for a two-step process (Scheme 6, b).[2a]
Unfortunately the cyclization-arylation conditions were not
tolerated in this reaction (entry 1). Pleasingly one set of condi-
tions (entry 4) led to efficient morpholine coupling, however at
elevated temperatures cf. literature precedent.[9] Application of
these conditions to the pharmaceutical intermediate (8) proved
successful manifesting comparable efficiency to the test sub-
strate (Scheme 7). This granted access to linezolid in a 77 %
yield with a total synthesis yield of 22 % for the final product
from ethyl carbamate 3. This yield is lower than the current
synthetic route to linezolid.[2c] Despite this, currently the mor-
pholine structure was introduced in the first step, whereas here
it is installed in the final step. Due to this, ease of variation
and analogue generation of the (C) ring would be significantly
improved using this synthetic strategy.
Scheme 7. Copper-catalyzed amination of linezolid intermediate.
Scheme 6. Acetyl deprotection and subsequent activation by nosylation; Ns-
Cl = 4-nitrobenzenesulfonyl chloride.
For the synthesis of tedizolid, the pharmaceutical intermedi-
ate (6) can again be utilized. This shows the high value of late
stage catalytic modifications to create different pharmaceuti-
cally active motifs. In this case a different coupling strategy
must be used to install the pyridyl-tetrazole motif to tedizolid.
The unsubstituted tetrazole ring was furnished using a dipo-
Due to the high value of this final intermediate, investiga-
tions into the cross coupling of the aryl iodide with morpholine
were performed using 4-iodoansiole as an electronic mimic of
the electron-donating oxazolidinone heterocycle. Similar reac-
tion conditions from the literature were sought and adapted lar cycloaddition reaction under acidic conditions. Unfortu-
for this transformation employing both copper and palladium nately subsequent selective methylation was not possible and
catalysis (Table 2).[7–10]
a mixture of isomers was observed (Scheme 8, a).[3b] Despite
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this, they were fully separable by standard chromatographic and arylation was used to construct the para-bromo motif. This
techniques. Following clean isolation of the tetrazole isomer it was achieved in excellent yields with complete selectivity for
was decided to install a boronic ester group to prime the struc- C–I over C–Br coupling. (Scheme 10, a). It was then proposed
ture for cross coupling (Scheme 8, b).[11a] This was carried out that a Buchwald–Hartwig amination would allow coupling of
using palladium catalysis and afforded the coupling partner in the morpholine-3-one heterocycle to install the (C) ring of rivar-
good yield. This was then followed by the palladium-catalyzed oxaban (Scheme 10, b). Despite this, two traditional palladium-
Suzuki–Miyaura reaction with the pharmaceutical intermediate catalyzed protocols gave rise to no conversion to product.[10]
6 (Scheme 9).[11]
Scheme 8. Formation of pyridyl-tetrazole coupling partner.
Scheme 10. (a) Copper-catalyzed construction of a para-bromo pharmaceuti-
cal intermediate. L1 = 2,2,6,6-tetramethyl-3,5-heptanedione (b) Palladium-
catalyzed amidation of intermediate.
Copper-catalyzed cross coupling would be significantly more
challenging as the structure would require C–Br activation and
the aromatic is electron-rich. Due to this, the para-iodo substi-
tuted intermediate was investigated as a more amenable inter-
mediate for copper-catalyzed amidations. The cyclization and
arylation methodology was carried out with diiodobenzene and
fortunately there was only minor oxazolidinone di-arylation ob-
served (Scheme 11). This was rationalized as due to the elec-
tron-donating ability of the oxazolidinone, the electron-rich
mono-amidated product was less amenable to act as a coupling
partner than diiodobenzene.
Scheme 9. Palladium-catalyzed Suzuki–Miyaura coupling followed by acetyl
deprotection to give tedizolid.
This reaction led to some deprotection of the acetyl protect-
ing group therefore a post-synthetic deprotection was carried
out to give the unprotected alcohol structure of tedizolid in a
total 77 % yield over two steps. The total yield for this synthesis
was 61 % from the synthetic pool of ethyl carbamate 3. This is
significantly higher than the current reported synthesis, prima-
rily due to a much more efficient Suzuki–Miyaura coupling cf.
Stille coupling previously reported.[11]
The final target drug molecule to be synthesized was the
anticoagulant rivaroxaban. This core structure bears similarities
to that previously used however there is no meta-fluoro substit-
Scheme 11. Copper-catalyzed cyclization and arylation of diiodobenzene.
uent on the (B) ring. Therefore the copper-catalyzed cyclization
L1 = 2,2,6,6-tetramethyl-3,5-heptanedione.
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Due to the success shown earlier for using 4-iodoanisole as a). However the second set of conditions used gave the ami-
a test substrate for the para-substituted oxazolidinone aromatic dated product in quantitative conversion.[7] These conditions
it was again used in the investigation of copper-catalyzed amid- were then applied to the API and pleasingly, an excellent yield
ation techniques. The cyclization and arylation conditions were of cross coupled product was observed (Scheme 12, b).
again studied with this coupling partner, however only trace
conversion was found using H NMR spectroscopy (Scheme 12,
Treatment of the silyl ether group with tetrabutylammonium
fluoride solution and subsequent synthesis of the activated al-
cohol structure was achieved in excellent yield of 83 % for a
two-step process (Scheme 13, a). Following this displacement
of the nosylate with a primary amine was again achieved with
aqueous ammonium hydroxide. This amine was again tele-
scoped through to an amide coupling with a preformed acid
chloride (Scheme 13, b). This gave rivaroxaban in 68 % over the
two steps. The total synthesis yield for rivaroxaban was 40 %
from the ethyl carbamate pool which is comparable to the cur-
rent reported yield of 39 %.[4c]
1
Conclusions
Three oxazolidinone-based API's used in the treatment of a
wide scope of diseases were synthesized via novel synthetic
strategies and constructed primarily utilizing cost-effective and
environmentally sustainable copper catalysis. All synthetic
routes used the copper-catalyzed one-pot cyclization and aryla-
tion methodology as the key synthetic step to construct the
core of these drug motifs. Antibacterial linezolid was synthe-
sized in a 22 % overall yield with seven steps from the silyl-
protected ethyl carbamate. Second generation antibacterial te-
dizolid was synthesized in a 61 % overall yield from the silyl
protected ethyl carbamate, heavily improving on current litera-
ture synthesis of this compound. Anticoagulant rivaroxaban was
synthesized in a 40 % overall yield from silyl protected ethyl
carbamate.
Scheme 12. Copper-catalyzed amination of test motif and application to API.
L1 = 2,2,6,6-tetramethyl-3,5-heptanedione, L2 = ethylenediamine [a] Conver-
sion by 1H NMR spectroscopy. [b] Isolated yield.
Experimental Section
General Information: All reactions used solvents and reagents as
obtained from commercial sources without further purification. Re-
actions requiring anhydrous conditions were performed under ni-
trogen in oven-dried apparatus. Dry solvents were obtained from
the SPS system. Solvents were removed under reduced pressure by
Büchi rotorvapor apparatus. All temperatures quoted are external.
1H, 13C and 19F NMR spectra were recorded on a Bruker Advance
300.22 MHz spectrometer or on an Agilent Technologies spectrome-
ter 500 MHz at 303 K. The spectra were recorded in CDCl3 solvent
and chemical shifts are reported relative to the residual CDCl3 sol-
vent peak as an internal standard unless otherwise stated. Data are
reported as follows: Chemical shift multiplicity (s = singlet, d = dou-
blet, t = triplet, q = quartet, m = multiplet), Chemical shifts are
reported in parts per million (ppm) and all coupling constants, J,
are reported in Hertz. Infra-red spectrum were recorded on a Perki-
nElmer 100 FT-IR spectrometer using a Universal ATR accessory for
sampling with only selected absorbencies quoted as νmax = in cm–
˜
1. Mass Spectra were recorded using an electrospray Time-of-Flight
MicroTOFTM mass spectrometer with acetonitrile as the solvent.
Masses were recorded in either positive or negative mode. Normal
phase flash chromatography was performed under medium pres-
sure using Fischer 60 Å silica gel (35–70 μm). Samples were loaded
as saturated solutions in an appropriate solvent system. Analytical
thin layer chromatography (TLC) was performed using aluminium-
Scheme 13. Synthesis of Rivaroxaban through late stage FGI's.
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backed plates coated with Alugram® SIL G/UV254 purchased from
96 °C. IR (thin film): νmax = 2953, 2928, 2856, 1747 (C=O), 1132, 834
˜
1
Macherey–Nagel and visualised by UV light (254 nm), and/or KMnO4 cm–1. H NMR (500 MHz, CDCl3): δ = 7.44 (dt, J = 11.3, 2.3 Hz, 1 H,
staining. Optical rotations were measured using an Optical Activity
ArH), 7.31 (td, J = 8.2, 6.5 Hz, 1 H, ArH), 7.24 (ddd, J = 8.3, 2.2, 0.9 Hz,
Ltd. AA-10 automatic polarimeter. Solutions were prepared in 2 mL 1 H, ArH), 6.81 (tdd, J = 8.2, 2.5, 0.9 Hz, 1 H, ArH), 4.67 (dddd, J =
samples of CHCl3, cell volume 1.5 mL, cell path length 1 dm. Meas- 8.9, 5.6, 4.1, 3.3 Hz, 1 H, OCH), 4.02 (t, J = 8.7 Hz, 1 H, NCH2), 3.93
urements were performed at room temperature, approx. 23 °C.
(dd, J = 8.5, 5.6 Hz, 1 H, CH2OSi), 3.90 (dd, J = 11.4, 4.1 Hz, 1 H,
NCH2), 3.79 (dd, J = 11.3, 3.3 Hz, 1 H, CH2OSi), 0.84 [s, 9 H, SiC(CH3)3],
0.07 [s, 6 H, Si(CH3)2] ppm. 13C NMR (126 MHz, CDCl3): δ = 163.1 (d,
J = 244.7 Hz), 154.6, 140.0 (d, J = 10.7 Hz), 130.2 (d, J = 9.3 Hz),
113.2 (d, J = 2.9 Hz), 110.6 (d, J = 21.3 Hz), 105.7 (d, J = 27.0 Hz),
72.5, 63.5, 46.7, 25.8, 18.2, –5.3 (d, J = 7.8 Hz) ppm. 19F NMR
(470 MHz, CDCl3): δ = –111.21 (ddd, J = 11.4, 8.2, 6.6 Hz) ppm.
HRMS (ESI): m/z calculated for C16H24NO3SiF requires 326.1587 for
[M + H]+: found: 326.1565.
Ethyl (2,3-Dihydroxypropyl)carbamate (2):[5] A solution of 3-
aminopropane-1,2-diol (9.11 g, 100 mmol) in water (20 mL) was
prepared in a round-bottomed flask. NaHCO3 (12.6 g, 150 mmol)
was added to the solution followed by CH2Cl2 (200 mL) to form a
biphasic mixture. The mixture was vigorously stirred at room tem-
perature before ethyl chloroformate (11.4 g, 9.9 mL, 105 mmol) was
added drop wise. Following complete addition, the reaction mixture
was vigorously stirred at room temperature for 2 h. After this time
the contents of the reaction vessel were concentrated under re-
duced pressure. The crude residue was suspended in acetone, fil-
tered and dried (MgSO4). The crude material was then purified by
flash silica gel chromatography (eluent: 100 % EtOAc) to give the
[3-(3-Fluoro-4-iodophenyl)-2-oxooxazolidin-5-yl]methyl Acetate
(6): To a solution of 5-{[(tert-butyldimethylsilyl)oxy]methyl}-3-(3-
fluorophenyl)oxazolidin-2-one (3.95 g, 12.14 mmol) in acetic acid
(50 mL) was added iodine monochloride (1.82 mL, 36.42 mmol).
The reaction mixture was stirred at room temperature for 5 h. After
this time the reaction mixture was concentrated under reduced
pressure. The crude oil was quenched with satd. NaHCO3 solution
(30 mL) and extracted with CH2Cl2 (200 mL). The organics were
washed with satd. sodium thiosulfate solution (2 × 50 mL), and the
organics were dried (MgSO4), filtered and concentrated under re-
duced pressure. The resulting crude solid was purified by flash silica
gel chromatography (eluent: 50 % EtOAc/hexanes) to give the title
compound as a white solid (3.76 g, 82 %), m.p. 118–120 °C. IR (thin
desired product. Pale yellow oil (91 %, 14.84 g). IR (thin film) νmax
=
˜
3338, 2984, 2936, 1683 (C=O), 1531 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 5.88 (t, J = 5.7 Hz, 1 H, NH), 4.11–4.04 (m, 4 H, OH, CH2CH3)
3.80–3.68 (m, 1 H, CHOH), 3.54 (ddd, J = 17.4, 11.7, 4.9 Hz, 2 H,
NHCH2), 3.35–3.03 (m, 2 H, CH2OH), 1.21 (t, J = 7.1 Hz, 3 H, CH2CH3)
ppm. 13C NMR (75 MHz, CDCl3): δ = 158.1, 71.2, 63.8, 61.3, 43.2, 14.6
ppm. HRMS (ESI): m/z calculated for C6H13NO4 requires 186.0742 for
[M + Na]+: found: 186.0770.
film): νmax = 2970, 1742 (C=O), 1481, 1224 cm–1. 1H NMR (500 MHz,
Ethyl
{3-[(tert-Butyldimethylsilyl)oxy]-2-hydroxypropyl}carb-
˜
amate (3):[5] To a solution of ethyl (2,3-dihydroxypropyl)carbamate
(8.159 g, 50 mmol), in CH2Cl2 was added triethylamine (8.40 mL,
60 mmol) and DMAP (0.239 g, 1.96 mmol). The solution was cooled
to 0 °C in an ice-water bath before the portion wise addition of
tert-butylchlorodimethylsilane (8.290 g, 55 mmol). The reaction mix-
ture was stirred at 0 °C for 1 h before warming to 40 °C for a
further 4 h. After this time the contents of the reaction vessel were
concentrated under reduced pressure, suspended with EtOAc
(50 mL), filtered and concentrated under reduced pressure. The re-
sulting crude oil was purified by flash silica gel chromatography
(eluent: 0–40 % EtOAc/hexanes) The desired fraction were concen-
trated under reduced pressure to give the title compound as a pale
CDCl3): δ = 7.70 (dd, J = 8.7, 7.1 Hz, 1 H, ArH), 7.47 (dd, J = 10.2,
2.6 Hz, 1 H, ArH), 7.06 (dd, J = 8.7, 2.5 Hz, 1 H, ArH), 4.88 (dddd, J =
8.9, 6.2, 4.8, 4.0 Hz, 1 H, OCH), 4.37 (dd, J = 12.3, 3.9 Hz, 1 H, AcCH2),
4.30 (dd, J = 12.3, 4.9 Hz, 1 H, AcCH2), 4.10 (t, J = 9.0 Hz, 1 H, NCH2),
3.80 (dd, J = 8.9, 6.3 Hz, 1 H, NCH2), 2.09 (s, 3 H, CO2CH3) ppm. 13C
NMR (126 MHz, CDCl3): δ = 170.6, 162.0 (d, J = 244.6 Hz), 153.7,
139.9 (d, J = 9.9 Hz), 139.4 (d, J = 3.0 Hz), 115.0 (d, J = 3.3 Hz), 106.0
(d, J = 29.7 Hz), 74.4 (d, J = 25.8 Hz), 70.2, 64.0, 46.9, 20.7 ppm. 19F
NMR (470 MHz, CDCl3): δ = –91.44 (dd, J = 10.1, 7.2 Hz) ppm. HRMS
(ESI): m/z calculated for C12H11NO4FI requires 379.9795 for [M + H]+:
found: 379.9774.
[3-(3-Fluoro-4-iodophenyl)-2-oxooxazolidin-5-yl]methyl 4-
Nitrobenzenesulfonate (7): To a suspension of potassium carb-
onate (0.829 g, 6 mmol) in 3:1 MeOH/CH2Cl2 (45 mL) was added [3-
(3-fluoro-4-iodophenyl)-2-oxooxazolidin-5-yl]methyl acetate
(1.504 g, 4 mmol). The reaction mixture was stirred at room temper-
ature for 25 min. The reaction mixture was neutralised with AcOH
(0.5 mL) and water (26 mL). MeOH was removed under reduced
pressure and the aqueous solution was extracted with CH2Cl2 (2 ×
100 mL). The organics were combined, dried (MgSO4), filtered and
concentrated to give a crude glassy product. The crude material was
purified by flash silica gel chromatography (eluent: 100 % EtOAc) to
yellow oil (84 %, 11.65 g). IR (thin film): νmax = 3347, 2953, 2930,
˜
1
2886, 2858, 1694 (C=O), 1523 cm–1. H NMR (300 MHz, CDCl3): δ =
5.13 (s, 1 H, NH), 4.11 (q, J = 7.1 Hz, 2 H, CH2CH3), 3.80–3.69 [m, 1
H, (OH)CH], 3.64 (dd, J = 10.1, 4.5 Hz, 1 H, CH2OSi), 3.53 (dd, J =
10.1, 6.1 Hz, 1 H, CH2OSi), 3.40 (ddd, J = 13.7, 6.6, 3.5 Hz, 1 H, NCH2),
3.15 (ddd, J = 13.9, 6.8, 5.2 Hz, 1 H, NCH2), 1.23 (t, J = 7.1 Hz, 3 H,
CH2CH3), 0.89 [s, 9 H, SiC(CH3)3], 0.11–0.01 [s, 6 H, Si(CH3)2] ppm.
13C NMR (75 MHz, CDCl3): δ = 157.5, 71.2, 64.8, 61.1, 43.7, 25.9,
18.4, 14.7, –5.3 (d, J = 1.1 Hz) ppm. HRMS (ESI): m/z calculated for
C12H27NO4Si requires 278.1787 for [M + H]+: found: 278.1772.
5-{[(tert-Butyldimethylsilyl)oxy]methyl}-3-(3-fluorophenyl)- give the free alcohol structure. (1.23 g, 91 %), m.p. 116–117 °C
oxazolidin-2-one (5): To a solution of ethyl {3-[(tert-butyldimethyl- (ref.[12] 116–117 °C). IR (thin film): νmax = 3439, 2971, 1740 (C=O),
˜
silyl)oxy]-2-hydroxypropyl}carbamate (2.77 g, 10 mmol), 3-fluoro- 1480, 1228 cm–1
.
1H NMR [500 MHz, (CD3)2SO]: δ = 7.82 (dd, J =
iodobenzene (1.76 mL, 15 mmol) and 2,2,6,6-tetramethylheptane- 8.6, 7.6 Hz, 1 H, ArH), 7.58 (dd, J = 11.0, 2.5 Hz, 1 H, ArH), 7.22 (dd,
3,5-dione (0.44 mL, 2 mmol) in MeCN (40 mL) was added cesium
carbonate (6.52 g, 20 mmol) and copper iodide (0.190 g, 1 mmol).
J = 8.7, 2.4 Hz, 1 H, ArH), 5.21 (t, J = 5.5 Hz, 1 H, OH), 4.72 (dq, J =
6.3, 3.7 Hz, 1 H, OCH), 4.07 (t, J = 9.0 Hz, 1 H, NCH2), 3.82 (dd, J =
The reaction mixture was heated to 80 °C for 20 h. After this time, 8.9, 6.2 Hz, 1 H, NCH2), 3.67 (ddd, J = 12.3, 5.2, 3.4 Hz, 1 H, CH2OH),
the mixture was cooled to room temperature and was then diluted 3.55 (ddd, J = 12.3, 5.4, 4.2 Hz, 1 H, CH2OH) ppm. 13C NMR [126 MHz,
with EtOAc (50 mL). The resulting suspension was filtered through
a short plug of silica (eluent: 100 % EtOAc). The crude filtrate was
concentrated under vacuum and the resulting oil was purified by
flash silica gel chromatography (eluent: 30 % EtOAc/hexanes) to
give the title compound as a white solid (2.66 g, 91 %), m.p. 95–
(CD3)2SO]: δ = 161.1 (d, J = 240.2 Hz), 154.2, 140.5 (d, J = 10.3 Hz),
139.0 (d, J = 3.4 Hz), 115.4 (d, J = 3.0 Hz), 105.1 (d, J = 29.8 Hz),
73.8 (d, J = 26.1 Hz), 73.3, 61.5, 45.9 ppm. 19F NMR [470 MHz,
(CD3)2SO]: δ = –93.88 (dd, J = 10.9, 7.5 Hz) ppm. HRMS (ESI): m/z
calculated for C10H9NO3FI requires 337.9689 for [M + H]+: found:
Eur. J. Org. Chem. 2016, 1305–1313
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337.9671. To a solution the above solid (1.14 g, 3.4 mmol) in triethyl-
amine (0.95 mL, 6.8 mmol) and CH2Cl2 (50 mL) was added 4-nitro-
benzenesulfonyl chloride (0.909 g, 4.1 mmol) portion-wise at room
temperature. The reaction mixture was stirred for 5 h. The reaction
washed with EtOAc (150 mL). The organics were combined, dried
(MgSO4), filtered and concentrated to give a crude oil. The oil was
purified by flash silica gel chromatography (eluent: 5–30 % acetone/
CH2Cl2) to give the title compound as a white solid (0.260 g, 77 %),
mixture was then quenched with water (50 mL) and diluted with m.p. 187–189 °C. IR (thin film): νmax = 3280, 2855, 1739 (C=O), 1732
˜
CH2Cl2 (150 mL). The organics were then washed with water (2 × (C=O), 1516, 1231 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.43 (dd, J =
20 mL). The organics were then dried (MgSO4), filtered and concen- 14.3, 2.6 Hz, 1 H, ArH), 7.07 (ddd, J = 8.8, 2.6, 1.1 Hz, 1 H, ArH), 6.91
trated to give a crude yellow solid. The yellow solid was then tritu- (t, J = 9.1 Hz, 1 H, ArH), 6.27 (t, J = 6.1 Hz, 1 H, NH), 4.76 (dddd, J =
rated with Et2O/Hexane (20 mL) to give the title compound as a
pale yellow solid (1.73 g, 97 %), m.p. 149–151 °C. IR (thin film):
8.9, 6.7, 5.8, 3.3 Hz, 1 H, OCH), 4.01 (t, J = 9.0 Hz, 1 H, 1 H, NHCH2),
3.89–3.84 (m, 4 H, 4 H, OCH2), 3.75 (dd, J = 9.1, 6.7 Hz, 1 H, 1 H,
νmax = 1743 (C=O), 1527, 1417, 123 cm–1 1H NMR [500 MHz, NHCH2), 3.68 (ddd, J = 14.7, 6.1, 3.3 Hz, 1 H, 1 H, ArNCH2), 3.64–3.57
.
˜
(CD3)2SO]: δ = 8.44 (d, J = 8.8 Hz, 2 H, ArH), 8.19 (d, J = 8.8 Hz, 2 H, (m, 1 H, 1 H, ArNCH2), 3.07–3.01 (m, 4 H, 4 H, NCH2), 2.01 [s, 3 H,
ArH), 7.85–7.76 (m, 1 H, ArH), 7.48 (dd, J = 10.8, 2.3 Hz, 1 H, ArH),
7.12 (dd, J = 8.7, 2.3 Hz, 1 H, ArH), 4.96 (td, J = 9.1, 5.5 Hz, 1 H,
N(O)CH3] ppm. 13C NMR (126 MHz, CDCl3): δ = 171.2, 155.6 (d, J =
246.7 Hz), 154.4, 136.7 (d, J = 8.8 Hz), 133.0 (d, J = 10.4 Hz), 118.9
OCH), 4.56–4.44 (m, 2 H, NsOCH2), 4.11 (t, J = 9.4 Hz, 1 H, NCH2), (d, J = 4.2 Hz), 114.0 (d, J = 3.4 Hz), 107.6 (d, J = 26.4 Hz), 72.0, 67.0,
3.70 (dd, J = 9.3, 6.1 Hz, 1 H, NCH2) ppm. 13C NMR [126 MHz, 51.1 (d, J = 3.2 Hz), 47.8, 42.1, 23.2 ppm. 19F NMR (470 MHz, CDCl3):
(CD3)2SO]: δ = 161.1 (d, J = 240.4 Hz), 154.3, 153.2, 150.7, 139.9 (d,
δ = –120.13 (dd, J = 14.3, 9.5 Hz) ppm. HRMS (ESI): m/z calculated
J = 10.3 Hz), 139.0 (d, J = 3.4 Hz), 129.4, 124.9, 115.5 (d, J = 3.1 Hz), for C16H70N3O4F requires 338.1516 for [M + H]+: found: 338.1493.
105.3 (d, J = 29.9 Hz), 74.4 (d, J = 26.1 Hz), 71.3, 69.9, 45.6 ppm. 19F
5-Bromo-2-(2H-tetrazol-5-yl)pyridine (10): A mixture of 5-bromo-
NMR [470 MHz, (CD3)2SO]: δ = –93.39 (dd, J = 10.7, 7.5 Hz) ppm.
picolinonitrile (0.366 g, 2.0 mmol), sodium azide (0.156 g, 2.4 mmol)
HRMS (ESI): m/z calculated for C16H12N2O7SFI requires 544.9291 for
and ammonium chloride (0.106 g, 2.0 mmol) was heated in DMF
[M + Na]+: found: 544.9305.
(4 mL) at 120 °C for 1 h. The reaction mixture was cooled to room
N-{[3-(3-Fluoro-4-iodophenyl)-2-oxooxazolidin-5-yl]methyl}-
acetamide (8): [3-(3-fluoro-4-iodophenyl)-2-oxooxazolidin-5-yl]-
methyl 4-nitrobenzenesulfonate (1.73 g, 3.31 mmol) was partially
dissolved in MeCN (15 mL) in a 100 mL pear-shaped Schlenk flask.
NH4OH (30 wt.-% NH3) solution (20 mL) was added and the vessel
was sealed and heated to 80 °C for 5 h. The reaction mixture was
cooled to room temperature and the pressure from the vessel was
released. The contents of the flask were then concentrated under
reduced pressure to dryness to give a crude yellow solid. The crude
amine was dissolved in dry CH2Cl2 (50 mL) and cooled in an ice-
water bath to 0 °C. Triethylamine (1.38 mL, 9.93 mmol) was added
followed by the portion wise addition of acetyl chloride (0.47 mL,
6.62 mmol). The reaction mixture was warmed to room temperature
and left to stir overnight. After this time the reaction mixture was
concentrated under reduced pressure and dissolved in 1:1 MeOH/
CH2Cl2 and absorbed on to silica. The crude reaction mixture was
purified by flash silica gel chromatography (eluent: 90:10 EtOAc/
MeOH) to give the title compound as a white solid (0.507 g, 41 %),
temperature before being diluted with EtOAc (20 mL). The resulting
suspension was filtered under reduced pressure, the solids were
washed with EtOAc and dried to give the title compound as a
1
brown solid (0.380 g, 84 %). H NMR [500 MHz, (CD3)2SO]: δ = 8.69
(d, J = 2.1 Hz, 1 H, ArH), 8.09 (dd, J = 8.5, 2.4 Hz, 1 H, ArH), 7.99 (d,
J = 8.5 Hz, 1 H, ArH), 7.30 (s, 1 H, NH) ppm. Crude compound 10
was used in later steps without further purification.
5-Bromo-2-(1-methyl-1H-tetrazol-5-yl)pyridine (11a) and 5-
Bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (11):[3b] A solution
of 5-bromo-2-(2H-tetrazol-5-yl)pyridine (1.71 g, 7.6 mmol) and
NaOH (1.36 g, 34 mmol) in dry DMF (15 mL) were stirred at room
temperature for 3 h. The reaction mixture was concentrated to dry-
ness and the solids were re-dissolved in dry DMF (12 mL). The sus-
pension was treated with MeI (0.811 mL, 13 mmol) dropwise at 0 °C.
The reaction mixture was warmed to room temperature for 2 h. The
reaction mixture was then partitioned between water and EtOAc.
The organics were washed with water (2 × 20 mL), dried (MgSO4),
filtered and concentrated under reduced pressure. The residue was
then purified by flash silica gel chromatography (eluent 40 %
EtOAc/hexanes) to give the two regio-isomers.
m.p. 153–154 °C. IR (thin film): νmax = 3326, 2971, 1741 (C=O), 1655
˜
(C=O), 1374, 1217 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.67 (dd, J =
8.7, 7.1 Hz, 1 H, ArH), 7.45 (dd, J = 10.2, 2.5 Hz, 1 H, ArH), 6.98 (dd,
J = 8.7, 2.5 Hz, 1 H, ArH), 6.40 (t, J = 5.7 Hz, 1 H, NH), 4.79 (ddt, J =
8.8, 6.7, 4.4 Hz, 1 H, OCH), 4.02 [t, J = 9.0 Hz, 1 H, CH2N(O)], 3.77
[dd, J = 9.1, 6.8 Hz, 1 H, CH2N(O)], 3.65 (dd, J = 7.7, 3.6 Hz, 2 H,
NCH2), 2.01 [s, 3 H, N(O)CH3] ppm. 13C NMR (126 MHz, CDCl3): δ =
171.3, 162.0 (d, J = 244.6 Hz), 154.1, 139.8 (d, J = 9.9 Hz), 139.4 (d,
J = 2.9 Hz), 115.1 (d, J = 3.3 Hz), 106.1 (d, J = 29.7 Hz), 74.5 (d, J =
26.0 Hz), 72.2, 47.4, 41.9, 23.1 ppm. 19F NMR (470 MHz, CDCl3): δ =
–91.43 (dd, J = 10.2, 7.2 Hz) ppm. HRMS (ESI): m/z calculated for
C12H12N2O3FI requires 378.9954 for [M + H]+: found: 378.9936.
11a: White solid (0.294 g, 17 %), m.p. 168–170 °C. IR (thin film):
1
νmax = 2970, 1446, 1379 cm–1. H NMR (500 MHz, CDCl3): δ = 8.79
˜
(d, J = 2.3 Hz, 1 H, ArH), 8.26 (dd, J = 8.5, 0.6 Hz, 1 H, ArH), 8.05 (dd,
J = 8.4, 2.3 Hz, 1 H, ArH), 4.48 (s, 3 H, NCH3) ppm. 13C NMR (126 MHz,
CDCl3): δ = 151.6, 150.8, 143.4, 140.3, 125.6, 123.1, 37.1 ppm. HRMS
(ESI): m/z calculated for C7H6BrN5 requires 239.9884 for [M + H]+:
found: 239.9863.
11: White solid (0.282 g, 15 %), m.p. 163–165 °C. IR (thin film) νmax
=
˜
2991, 1454, 1380 cm–1. H NMR (500 MHz, CDCl3): δ = 8.82 (s, 1 H,
ArH), 8.13 (d, J = 8.4 Hz, 1 H, ArH), 7.99 (dd, J = 8.4, 2.3 Hz, 1 H,
ArH), 4.44 (s, 3 H, NCH3) ppm. 13C NMR (126 MHz, CDCl3): δ = 164.3,
151.5, 145.2, 139.9, 123.5, 122.3, 39.8 ppm. HRMS (ESI): m/z calcu-
lated for C7H6BrN5 requires 261.9704 for [M + Na]+: found: 261.9685.
1
N-{[3-(3-Fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl]-
methyl}acetamide (Linezolid) (9):[13] A carousel tube was charged
with N-{[3-(3-fluoro-4-iodophenyl)-2-oxooxazolidin-5-yl]methyl}-
acetamide (0.378 g, 1 mmol), CuBr (0.029 g, 0.2 mmol), BINOL
(0.057 g, 0.2 mmol) and K3PO4 (0.425 g, 2.0 mmol). The tube was
flushed with argon before DMF (1 mL) and morpholine (0.131 g,
0.13 mL, 1.5 mmol) was charged in to the tube via syringe. The
reaction mixture was heated to 80 °C for 4 h. After this time the
reaction mixture was cooled to room temperature and diluted with
CH2Cl2 (200 mL). The organics were washed with brine (2 × 50 mL)
and water (50 mL). The aqueous washes were combined with
2-(2-Methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-di-
oxaborolan-2-yl)pyridine (12): To an oven dried carousel tube was
added 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (0.240 g,
1 mmol), bis(pinacolato)diboron (0.508 g, 2.0 mmol), KOAc (0.294 g,
3.0 mmol) and PdCl2(dppf) (0.073 g, 0.1 mmol). The solids were
purged with argon before DMSO was added via septum. The solu-
tion was further purged with argon before heating at 80 °C for 2 h.
Eur. J. Org. Chem. 2016, 1305–1313
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The reaction mixture was diluted with CH2Cl2 (50 mL) and washed
silyl)oxy]-2-hydroxypropyl}carbamate (2.77 g, 10 mmol), 1,4-diiodo-
with brine (2 × 50 mL), dried (Na2SO4), filterd and concentrated benzene (4.95 g, 15 mmol) and 2,2,6,6-tetramethylheptane-3,5-di-
under reduced pressure to give a brown solid. The solid was tritu- one (0.44 mL, 2 mmol) in MeCN (40 mL) was added cesium carb-
rated with Et2O, decanted and the residual solid dried under re- onate (6.52 g, 20 mmol) and copper iodide (0.190 g, 1 mmol). The
duced pressure to give the title compound as a grey solid (160 mg,
reaction mixture was heated to 80 °C for 20 h. After this time the
1H reaction mixture was cooled to room temperature and was diluted
with EtOAc (50 mL). Analysis of the crude reaction mixture by 1H
56 %). IR (thin film): νmax = 2978, 1600, 1356, 1224, 1097 cm–1
.
˜
NMR (500 MHz, CDCl3): δ = 9.08 (s, 1 H, ArH), 8.23 (s, 2 H, ArH), 4.46
(s, 3 H, NCH3), 1.38 [s, 12 H, 12 H, C(CH3)2] ppm. 11B NMR (160 MHz, NMR showed total consumption of the free-N oxazolidinone, where
CDCl3): δ = –5.5 ppm. HRMS (ESI): m/z calculated for C13H17N5O2B
a 13:1 mixture of mono:di arylated species were present. The result-
ing suspension was filtered through a short plug of silica (eluent:
100 % EtOAc). The crude filtrate was concentrated under vacuum
and the resulting oil was purified by flash silica gel chromatography
(eluent: 30 % EtOAc/hexanes) to give the title compound as an off
requires 288.1631 for [M + H]+: found: 288.1601.
3-{3-Fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl]phen-
yl}-5-(hydroxymethyl)oxazolidin-2-one [Tedizolid (13)]:[3b] An
oven-dried Schlenk tube was charged with 2-(2-methyl-2H-tetrazol-
5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
(0.160 g, 0.56 mmol), [3-(3-fluoro-4-iodophenyl)-2-oxooxazolidin-5-
yl]methyl acetate (0.193 g, 0.51 mmol), K2CO3 (0.155 g, 1.12 mmol)
and PdCl2(dppf) (0.037 g, 0.0504 mmol). The solids were degassed
with argon before the addition of dioxane/water (7:1) (8 mL). The
reaction mixture was degassed a further time before heating to
80 °C overnight. The reaction mixture was cooled to room tempera-
ture, diluted with CH2Cl2 (200 mL) and washed with water (2 ×
20 mL). The organics were dried (Na2SO4), filtered and concentrated
white solid (3.043 g, 78 %), m.p. 84–86 °C. IR (thin film): νmax = 1504
˜
1
(C=O), 1460 cm–1. H NMR (500 MHz, CDCl3): δ = 7.67–7.63 (m, 2 H,
ArH), 7.36–7.30 (m, 2 H, ArH), 4.69–4.64 (m, 1 H, OCH), 4.00 [t, J =
8.7 Hz, 1 H, (TBSO)CH2], 3.91 (ddd, J = 15.5, 8.5, 3.9 Hz, 2 H, NCH2),
3.78 [dd, J = 11.3, 3.2 Hz, 1 H, (TBSO)CH2], 0.84 [s, 9 H, SiC(CH3)3],
0.07 [s, 6 H, Si(CH3)2] ppm. 13C NMR (126 MHz, CDCl3): δ = 154.6,
138.3, 138.0, 119.9, 87.3, 72.5, 63.5, 46.5, 25.83 (d, J = 3.1 Hz), 18.2,
–5.30 (d, J = 6.9 Hz) ppm. HRMS (ESI): m/z calculated for
C16H24NO3ISi requires 434.0648 for [M + H]+: found: 434.0660.
under reduced pressure. The crude material was purified by flash 4-[4-(5-{[(tert-Butyldimethylsilyl)oxy]methyl}-2-oxooxazolidin-
silica gel chromatography (100 % EtOAc) to give the acetyl pro- 3-yl)phenyl]morpholin-3-one (15): To a solution of 5-{[(tert-
tected alcohol as a white solid (0.105 g, 50 %). IR (thin film): νmax
=
butyldimethylsilyl)oxy]methyl}-3-(4-iodophenyl)oxazolidin-2-one
˜
1745, 1730 cm–1
.
1H NMR [500 MHz, (CD3)2SO/CD3OD/CDCl3, (0.433 g, 1 mmol), morpholine-3-one (0.121 g, 1.2 mmol) and ethyl-
80:5:15]: δ = 8.93 (s, 1 H, ArH), 8.31 (d, J = 8.2 Hz, 1 H, ArH), 8.05 (d, enediamine (6 mg, 0.1 mmol) in dioxane (3 mL) was added potas-
J = 8.2 Hz, 1 H, ArH), 7.62 (dd, J = 12.8, 2.2 Hz, 1 H, ArH), 7.53 (t, J = sium phosphate tribasic (0.424 g, 2 mmol) and copper iodide
8.6 Hz, 1 H, ArH), 7.39 (dd, J = 8.5, 2.2 Hz, 1 H, ArH), 4.97–4.88 (m,
1 H, OCH), 4.47 (s, 3 H, NCH3), 4.41 (dd, J = 12.3, 3.9 Hz, 1 H, AcCH2),
4.34 (dd, J = 12.3, 4.9 Hz, 1 H, AcCH2), 4.18 (t, J = 9.0 Hz, 1 H, NCH2),
3.88 (dd, J = 8.9, 6.3 Hz, 1 H, NCH2), 2.12 (s, 3 H, CO2CH3) ppm. 13C
(19 mg, 0.1 mmol). The reaction mixture was heated to 100 °C for
16 h. After this time the reaction mixture was cooled to room tem-
perature and filtered through a short plug of celite (eluent: 100 %
EtOAc). The filtrate was concentrated under vacuum and the crude
NMR (126 MHz, CDCl3): δ = 170.6, 164.8, 160.2 (d, J = 249.1 Hz), reaction mixture was purified by flash silica gel chromatography
153.8, 149.9 (d, J = 3.5 Hz), 145.6, 139.9 (d, J = 10.9 Hz), 137.2 (d, (eluent: 60 % EtOAc/hexanes) to give the title compound as a white
J = 3.8 Hz), 132.3, 130.7 (d, J = 4.4 Hz), 122.1, 120.5 (d, J = 13.9 Hz), solid (364 mg, 90 %), m.p. 141–143 °C. IR (thin film): νmax = 2953,
˜
113.9 (d, J = 3.3 Hz), 106.5 (d, J = 28.5 Hz), 70.2, 64.0, 47.0, 39.8,
2929, 2857, 1744 (C=O), 1662 (C=O), 1515, 1226, 1127 cm–1. 1H NMR
20.7 ppm. 19F NMR (470 MHz, CDCl3): δ = –114.37 (dd, J = 12.5, (500 MHz, CDCl3): δ = 7.60 (d, J = 8.8 Hz, 2 H, ArH), 7.34 (d, J =
8.7 Hz) ppm. HRMS (ESI): m/z calculated for C19H17N6O4F requires 8.8 Hz, 2 H, ArH), 4.67 (dq, J = 5.6, 4.0 Hz, 1 H, OCH), 4.34 [s, 2 H,
435.1193 for [M + Na]+: found: 435.1242. To solution of the above OCH2C(O)], 4.04 (dd, J = 9.6, 6.0 Hz, 3 H, 3 H, CH2OSi, OCH2), 3.96
solid (105 mg, 0.28 mmol) in CH2Cl2 (1 mL) and MeOH (4 mL) was
(dd, J = 8.5, 5.8 Hz, 1 H, CH2OSi), 3.90 (dd, J = 11.3, 4.2 Hz, 1 H,
added K2CO3 (0.057 g, 0.42 mmol). The reaction mixture was stirred NCH2), 3.80 (dd, J = 11.3, 3.3 Hz, 1 H, NCH2), 3.77–3.73 (m, 2 H,
at room temperature for 1 h. After this time the reaction mixture
was diluted with CH2Cl2 (200 mL) and washed with water (2 ×
20 mL). The organics were separated and diluted with MeOH
NCH2), 0.85 [s, 9 H, SiC(CH3)3], 0.08 [d, J = 1.8 Hz, 6 H, Si(CH3)2] ppm.
13C NMR (126 MHz, CDCl3): δ = 166.9, 154.8, 137.2, 137.0, 126.2,
119.0, 72.5, 68.7, 64.2, 63.5, 49.8, 46.8, 25.8, 18.3, –5.28 (d, J = 8.4 Hz)
(15 mL), dried (MgSO4), filtered and concentrated to give the title ppm. HRMS (ESI): m/z calculated for C20H30N2O5Si requires 407.2002
compound as a white solid, (0.090 g, 96 %), no m.p., decomp.
for [M + H]+: found: 407.2001.
> 180 °C. (ref.[3b] 201 °C). IR (thin film) νmax = 3371, 1741 (C=O),
˜
{2-Oxo-3-[4-(3-oxomorpholino)phenyl]oxazolidin-5-yl}methyl 4-
Nitrobenzenesulfonate (17): A solution of 4-[4-(5-{[(tert-
butyldimethylsilyl)oxy]methyl}-2-oxooxazolidin-3-yl)phenyl]-
morpholin-3-one (2.39 g, 5.9 mmol) in THF (55 mL) was treated
1625, 1409 cm–1
.
1H NMR [500 MHz, (CD3)2SO]: δ = 8.82 (s, 1 H,
ArH), 8.19 (d, J = 8.1 Hz, 1 H, ArH), 8.00 (d, J = 8.4 Hz, 1 H, ArH),
7.65–7.60 (m, 1 H, ArH), 7.47 (t, J = 8.6 Hz, 1 H, ArH), 7.33 (dd, J =
8.6, 2.0 Hz, 1 H, ArH), 4.68 (td, J = 9.8, 3.7 Hz, 1 H, OCH), 4.39 (s, 3
H, NCH3), 4.04 [t, J = 8.9 Hz, 1 H, (HO)CH2], 3.94 [dd, J = 8.6, 6.4,
(HO Hz, 1 H)CH2], 3.77 (dd, J = 12.4, 3.6 Hz, 1 H, NCH2), 3.62 (dd,
J = 12.4, 3.7 Hz, 1 H, NCH2) ppm. 13C NMR [126 MHz, (CD3)2SO]: δ =
163.8, 159.3 (d, J = 245.6 Hz), 154.3, 149.4 (d, J = 3.9 Hz), 145.0,
140.5 (d, J = 11.4 Hz), 137.1 (d, J = 3.4 Hz), 131.6 (d, J = 1.8 Hz),
130.9 (d, J = 4.3 Hz), 122.0, 118.5 (d, J = 13.4 Hz), 114.0 (d, J =
2.2 Hz), 105.3 (d, J = 28.5 Hz), 73.4, 61.5, 45.9, 39.3 ppm. 19F NMR
[470 MHz, (CD3)2SO]: δ = –115.49 (dd, J = 12.9, 9.0 Hz) ppm. HRMS
(ESI): m/z calculated for C17H15N6O3F requires 371.1267 for [M + H]+:
found: 371.1254.
with tetra-N-butylammonium fluoride 1.0
M solution in THF (7.1 mL,
7.1 mmol). The reaction mixture was stirred at room temperature
overnight. The reaction mixture was then concentrated and the
crude mixture was purified by flash silica gel chromatography (elu-
ent: 6 % MeOH/CH2Cl2) to give the free alcohol compound as a
white solid (1.582 g, 92 %), m.p. 159–161 °C. IR (thin film): νmax
=
˜
3377, 1737 (C=O), 1644 (C=O), 1228 cm–1. 1H NMR (500 MHz, CDCl3):
δ = 7.60 (d, J = 9.0 Hz, 2 H, ArH), 7.35 (d, J = 8.9 Hz, 2 H, ArH), 4.74
(ddd, J = 12.5, 7.1, 3.7 Hz, 1 H, OCH), 4.34 [s, 2 H, OCH2C(O)], 4.06–
3.92 (m, 6 H, 6 H), 3.79–3.71 (m, 3 H, 3 H), 1.81 (s, 1 H, 1 H) ppm.
13C NMR (126 MHz, CDCl3): δ = 167.0, 154.7, 137.2, 137.0, 126.3,
5-{[(tert-Butyldimethylsilyl)oxy]methyl}-3-(4-iodophenyl)ox- 119.1, 72.9, 68.7, 64.2, 62.9, 49.8, 46.5 ppm. HRMS (ESI): m/z calcu-
azolidin-2-one (16): To a solution of ethyl {3-[(tert-butyldimethyl-
lated for C14H16N2O5 requires 293.1137 for [M + H]+: found:
Eur. J. Org. Chem. 2016, 1305–1313
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
293.1110. To a suspension of the above solid (1.582 g, 5.4 mmol)
and triethylamine (1.51 mL, 10.8 mmol) in dry CH2Cl2 (50 mL) was
added portion wise at room temperature 4-nitrobenzenesulfonyl
chloride (1.44 g, 6.5 mmol). The reaction mixture was left to stir at
room temperature overnight. After this time the reaction mixture
was concentrated under reduced pressure and diluted in the mini-
mum volume of 50:50 MeOH/CH2Cl2. The crude reaction mixture
was then absorbed on to silica and concentrated to dryness. The
reaction mixture was then purified by flash silica gel chromatogra-
phy (eluent: 10 % MeOH/CH2Cl2). The desired fractions were com-
bined, concentrated and the resulting crude solid was washed with
water. The solids were then dried in a 80 °C oven overnight to give
the title compound as a white solid (2.33 g, 90 %), no m.p., decomp.
Acknowledgments
The authors wish to thank the University of Bath, UK and the
British Engineering and Physical Sciences Research Council
(EPSRC), CDT in Sustainable Chemical Technologies for funding.
Keywords: Total synthesis · Homogeneous catalysis · Cross
coupling · Nitrogen heterocycles · Copper
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˜
1518, 1368, 1189 cm–1. 1H NMR [500 MHz, (CD3)2SO]: δ = 8.49–8.41
(m, 2 H, ArH), 8.23–8.15 (m, 2 H, ArH), 7.56–7.46 (m, 2 H, ArH), 7.43–
7.37 (m, 2 H, ArH), 4.95 (dtd, J = 9.0, 5.8, 2.9 Hz, 1 H, OCH), 4.50 (qd,
J = 11.4, 4.1 Hz, 2 H, 2 H), 4.19 [s, 2 H, OCH2C(O)], 4.14 (t, J = 9.4 Hz,
1 H, 1 H), 3.97 (dd, J = 5.8, 4.3 Hz, 2 H, 2 H), 3.78–3.67 (m, 3 H, 3 H)
ppm. 13C NMR [126 MHz, (CD3)2SO]: δ = 165.9, 153.5, 150.7, 140.1,
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45.7 ppm. HRMS (ESI): m/z calculated for C20H19N3O9S requires
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Oxo-3-[4-(3-oxomorpholino)phenyl]oxazolidin-5-yl}methyl 4-nitro-
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˜
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(CD3)2SO]: δ = 8.97 (t, J = 5.8 Hz, 1 H, NH), 7.69 (d, J = 4.1 Hz, 1 H,
ArH), 7.56 (d, J = 9.1 Hz, 2 H, ArH), 7.40 (d, J = 9.0 Hz, 2 H, ArH),
7.19 (d, J = 4.0 Hz, 1 H, ArH), 4.84 (dq, J = 8.9, 5.6 Hz, 1 H, OCH),
4.22–4.14 [m, 3 H, O(CH2)C(O), thiopheneC(O)NHCH2], 3.97 (dd, J =
5.8, 4.3 Hz, 2 H, ArNCH2), 3.85 [dd, J = 9.2, 6.1 Hz, 1 H, thiophe-
neC(O)NHCH2], 3.71 (dd, J = 5.7, 4.4 Hz, 2 H, NCH2), 3.60 (t, J =
5.7 Hz, 2 H, OCH2) ppm. 13C NMR [126 MHz, (CD3)2SO]: δ = 165.9,
160.7, 154.0, 138.4, 137.0, 136.4, 133.2, 128.4, 128.1, 125.9, 118.3,
71.3, 67.7, 63.4, 49.0, 47.4, 42.2 ppm. HRMS (ESI): m/z calculated for
C19H18N3O5SCl requires 436.0733 for [M + H]+: found: 436.0719.
Received: January 11, 2016
Published Online: February 9, 2016
Eur. J. Org. Chem. 2016, 1305–1313
www.eurjoc.org
1313
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim