Synthesis of new heterocyclic analogs of linezolid

Article abstract of DOI:10.1016/j.tetlet.2015.09.065

We have previously attempted to prepare 5-(4-morpholinyl)-2-aminothiophene (3) by reducing 5-(4-morpholinyl)-2-nitrothiophene (2), to prepare a precursor for the preparation of thienyloxazolidinones as potential linezolid-like antibiotics. This strategy failed, but allowed us to define an interesting reductive aromatization reaction. We have now succeeded in producing thienyloxazolidinones using an alternative strategy, initiating from 5-(4-morpholinyl)thiophene-2-carboxaldehyde (8). This Letter describes the synthesis of thienyloxazolidinone 14, which is a key intermediate for the preparation of new oxazolidinone antibiotics with a thiophene core.

Full text of DOI:10.1016/j.tetlet.2015.09.065

Tetrahedron Letters 56 (2015) 6056–6058
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of new heterocyclic analogs of linezolid
⇑
Son T. Nguyen, Bing Li, Norton P. Peet
Department of Chemistry, Microbiotix Inc., One Innovation Drive, Worcester, MA 01605, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 July 2015
Revised 12 September 2015
Accepted 16 September 2015
Available online 21 September 2015
We have previously attempted to prepare 5-(4-morpholinyl)-2-aminothiophene (3) by reducing
5-(4-morpholinyl)-2-nitrothiophene (2), to prepare a precursor for the preparation of thienyloxazolidi-
nones as potential linezolid-like antibiotics. This strategy failed, but allowed us to define an interesting
reductive aromatization reaction. We have now succeeded in producing thienyloxazolidinones using
an alternative strategy, initiating from 5-(4-morpholinyl)thiophene-2-carboxaldehyde (8). This Letter
describes the synthesis of thienyloxazolidinone 14, which is a key intermediate for the preparation of
new oxazolidinone antibiotics with a thiophene core.
Keywords:
Linezolid
Oxazolidinones
50S ribosome
Thienyloxazolidinones
Ó 2015 Elsevier Ltd. All rights reserved.
The oxazolidinones comprise an important class of Gram-
positive antibiotics. The oxazolidinone class inhibits bacterial
protein synthesis by a unique mechanism of action that involves
binding to the 23S portion of the 50S ribosomal subunit and inhi-
bition of the formation of N-formylmethionine, which is necessary
for the translation process. Linezolid, the first oxazolidinone
antibiotic, is a parental drug with excellent oral bioavailability
and favorable pharmacokinetic properties.1
Linezolid was discovered by Barbachyn and colleagues at
Pharmacia and Upjohn in the 1990s, and was identified for
development through structure–activity, safety, tolerability, and
pharmacokinetic studies.2–6 Linezolid is the only agent in the oxa-
zolidinone class that was marketed until 2014, when tedezolid7
was approved for skin infections. Other oxazolidinones in later
stages of development include radezolid,8 posizolid,9 sutezolid,10
eperezolid,11 and ranbezolid.12
needed. With modeling studies, based on the known crystal struc-
ture of linezolid bound to the 50S ribosomal subunit,24 we have
shown that thienyl analogs of linezolid do indeed dock into the
linezolid binding site, and the binding position suggests that a
resistance profile for these new antibiotics might be improved with
respect to linezolid. This report describes the synthesis of a key
thienyloxazolidinone intermediate that allows access to thiophene
analogs of linezolid. Challenges encountered in the synthesis of
this key intermediate explain why these analogs have not previ-
ously been reported.
We previously described the attempted preparation of
2-amino-5-(4-morpholinyl)thiophene (3), as briefly summarized
in Scheme 1.25 It was straightforward to prepare the corresponding
2-nitro compound 2 from 2-bromo-5-nitrothiophene (1), by dis-
placement of bromide using morpholine. We determined that the
desired amino compound 3 was undoubtedly produced by reduc-
tion of the nitro group in 2 using catalytic hydrogenation condi-
tions, since we could trap the amino compound
3 as the
O
O
acetamide 5 when we performed the reduction of 3 using zinc in
acetic acid with added acetic anhydride. The product isolated from
the reduction of compound 2 was thioamide 4, which is actually
isomeric with compound 3. We envision the mechanism of this
remarkable dearomatization reaction, and the formation of the
unexpected thioamide 4, as shown in Scheme 1, where tautomer-
ization of 3 to imine 6 allows fragmentation of the thiophene ring
to cyano intermediate 7. Tautomerization of intermediate 7 can
then directly produce the observed thioamide 4.
O
N
N
O
S
N
N
O
O
NHCOCH3
OH
14
F
linezolid
thienyloxazolidinone
However, linezolid resistance has developed,13–18 which in
Gram-positive bacteria is usually driven by a point mutation of
the genes encoding for the 23S ribosomal RNA.19–23 New oxazolidi-
none structures that are less prone to resistance are therefore
Our inability to isolate aminothiophene 3 was quite surprising,
since the reduction of 4-(4-morpholinyl)nitrobenzene to
4-(4-morpholinyl)aniline is easily accomplished.26–28 We attribute
this difference to thiophenes possessing less aromatic character
⇑
Corresponding author. Tel.: +1 616 298 8483; fax: +1 616 298 7337.
E-mail address: nppeet@gmail.com (N.P. Peet).
http://dx.doi.org/10.1016/j.tetlet.2015.09.065
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

S. T. Nguyen et al. / Tetrahedron Letters 56 (2015) 6056–6058
6057
morpholine
THF
C
86%
Zn, Ac2O
AcOH
N
NO2
Br
NO2
S
N
NHAc
S
O
S
80 o
O
THF, toluene
41%
2
1
5
Pd/C, NH4HCO2
MeOH, THF
Zn
AcOH
61%
or Pd/C, H2, EtOH
S
N
CN
N
NH2
O
S
O
4
3
H
N
H
CN
4
N
N
N
N
S
S
SH
O
O
O
H
H
7
3
6
Scheme 1. Attempted synthesis of 2-amino-5-(4-morpholinyl)thiophene (3).
AgNO3
NaOH
(PhO)2P(O)N3
Et3N
O
C
N
CHO
N
CO2H
OTBS
N
N
S
S
S
O
O
O
EtOH, H2O
THF
65 o
C
60 o
C
8
9
10
73 %
86 %
O
O
O
TBAF
K2CO3
OH
10
O
N
N
O
N
N
H
N
N
O
S
Cl
OTBS
NPhth
S
S
THF
O
O
MeOH
reflux
80 %
O
toluene
reflux
43 %
reflux
37 %
OTBS
OH
11
Cl
13
12
14
O
O
O
10
OH
K2CO3
O
O
Cl
N
N
H
N
N
S
NPhth
S
toluene
reflux
29% (borsm)
O
MeOH
38%
O
N
O
15
Cl
16
17
Scheme 2. Synthesis of key intermediates for the preparation of thienyloxazolidinones.
than benzenes, and having more diene character. 2-Aminothio-
phenes are well-known compounds, and scores of these com-
pounds have been produced using the Gewald syntheses29,30 and
modified Gewald conditions.31–36
protected 3-chloro-2-hydroxypropylamine 1541 (racemic) was
converted to carbamate 16 by treatment with isocyanate 10, and
intramolecular alkylation gave the second key intermediate 17.
Syntheses of oxazolidinones 14 and 17 are highly significant,
since they represent key intermediates for the preparation of
thienyloxazolidinones that are new potential antibiotic agents.
The chemistry described in this report also makes possible the
preparation of other novel linezolid-like structures with electron-
rich five-membered rings that replace the phenyl core, such as
furanyloxazolidinones, as well as substituted versions of these
compounds.
Since the desired aminothiophene 3 was not a stable, isolable
compound, we sought a synthetic route in which the amino com-
pound would not be produced as a discrete intermediate. The
Curtius rearrangement37 is one that allows the conversion of an
aryl carboxylic acid, through the intermediacy of an acyl azide, to
an arylisocyanate, which can be viewed as a protected arylamine.
This route seemed attractive, since the required starting materials
were accessible. 5-(4-Morpholinyl)thiophene-2-carboxaldehyde
(8) was prepared as described38,39 by treatment of 5-bromothio-
phene-2-carboxaldehyde with morpholine in water. Treatment of
aldehyde 8 with silver nitrate produced the corresponding 5-(4-
morpholinyl)thiophene-2-carboxylic acid (9) in 73% yield.
Conversion of 9 to 2-isocyanato-5-(4-morpholinyl)thiophene (10)
was then accomplished in 86% yield by treatment with
diphenylphosphoryl azide, as shown in Scheme 2.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.09.
065.
References and notes
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intermediate 14 in 43% yield. In a similar fashion, the phthalamido
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