Synthesis of Oxazolidinones by a Hypervalent Iodine Mediated Cyclization of N-Allylcarbamates

Article abstract of DOI:10.1002/adsc.202001451

The preparation of oxazolidinones by the hypervalent iodine mediated cyclization of allylcarbamates is described. A versatile range of substrates can be converted into substituted oxazolidinones primed for further transformations. Derivatization of the products at both ends is demonstrated. A preliminary attempt at the enantioselective formation of an oxazolidinone using a chiral iodane is also presented. (Figure presented.).

Full text of DOI:10.1002/adsc.202001451

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DOI: 10.1002/adsc.202001451
Synthesis of Oxazolidinones by a Hypervalent Iodine Mediated
Cyclization of N-Allylcarbamates
Mirdyul Das,a Arantxa Rodríguez,a Pui Kin Tony Lo,a and Wesley J. Morana,*
a
Department of Chemistry
University of Huddersfield
Queensgate, Huddersfield HD1 3DH, U.K.
E-mail: w.j.moran@hud.ac.uk
Manuscript received: November 20, 2020; Revised manuscript received: January 17, 2021;
Version of record online: Februar 4, 2021
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202001451
© 2021 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH. This is an open access article under the
terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
of carbonylated aminoalcohols.[8] Ring expansion of
epoxides or aziridines into oxazolidinones is also a
Abstract: The preparation of oxazolidinones by the
hypervalent iodine mediated cyclization of allylcar-
common approach. For example, Toda and co-workers
bamates is described. A versatile range of substrates
reported the phosphonium salt catalyzed coupling of
can be converted into substituted oxazolidinones
epoxides and aryl isocyanates (Scheme 1b).[9] Aggar-
primed for further transformations. Derivatization of
wal and co-workers described the Pd-catalyzed ring-
the products at both ends is demonstrated. A
opening carbonylation of 2-vinylaziridines with carbon
preliminary attempt at the enantioselective forma-
dioxide (Scheme 1c).[10] Metal-catalyzed cyclization of
tion of an oxazolidinone using a chiral iodane is
allylcarbamates is also a widely utilized tactic, such as
also presented.
Liu and co-workers Pd-catalyzed aminohydroxylation
protocol (Scheme 1d).[11]
Our experience with developing hypervalent iodine
mediated cyclizations prompted us to develop a new
Keywords: Iodine; Addition to alkenes; Cyclization;
Hypervalent compounds; Allylic compounds; CÀ O
approach to oxazolidinones that complements existing
bond formation
methods.[12] Cyclization of N-allylcarbamates, medi-
Oxazolidinone antibiotics are useful in the treatment of
drug-resistant bacterial infections, especially tuber-
culosis which is still one of the top 10 causes of death
worldwide.[1] Linezolid 1 was the first such drug to
receive clinical approval and has a unique mode of
action which leads to bacterial protein synthesis
inhibition (Figure 1).[2] Numerous structurally related
compounds are clinically approved or in clinical trials
e.g. tedizolid 2,[3] delpazolid 3,[4] and AZD5847 4.[5]
A reported synthesis of linezolid 1, and related
compounds, involves formation of the oxazolidone
through reaction of an aniline with an epoxide to form
an aminoalcohol followed by carbonylative ring
closure (Scheme 1a).[6] Such carbonylation of amino
alcohols to generate oxazolidinone rings is a popular
Figure 1. Examples of oxazolidinone derivatives displaying
antibiotic and antimicrobial activities.
strategy with many examples and variations in the ated by a hypervalent iodine reagent, was envisaged as
literature.[7] A closely related strategy is the cyclization a useful addition to the synthetic canon (Scheme 1e).
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Table 1. Optimization of carbamate cyclization.
°
Entry
5
[O]
n
Solvent
T/ C
Yield/%[a]
1
2
3
4
5
6
7
8
5a
5b
5b
5b
5b
5b
5b
5b
5b
5a
5c
5d
5d
5d
5d
5d
5d
5d
5d
5d
5d
7
7
7
7
7
7
7
7
7
7
7
7
8
9
10
10
10
11
12
13
14
3
3
3
3
3
3
3
5
2
5
5
3
3
3
3
2
1.2
3
3
3
3
MeCN
MeCN
MeCN
DCE
MeOH
TFE
80
80
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
15 (6a)
36 (6b)
33 (6b)
31 (6b)
Mixture
48 (6b)
59 (6b)
67 (6b)
41 (6b)
22 (6a)
33 (6a)
76 (6a)
69 (6a)
66 (6a)
95 (6a)
90 (6a)
65 (6a)
Trace
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
9
10
11
12
13
14
15
16
17
18
19
20
21
Scheme 1. Strategies for oxazolidinone formation. CDI is
carbonyl diimidazole.
Notably, Minakata and co-workers reported a related
cyclization employing t-butyl hypoiodite with allyl
amines and CO2.[13] The popularity of using hyper-
valent iodine in synthesis has soared in recent years
because of the ease of use, the low cost and toxicity as
well as the plethora of useful reactivity that has been
uncovered.[14] Cariou and co-workers have reported the
cyclization of N-allylguanidines using Koser’s reagent
7,[15] and the cyclization of unsaturated N-alkoxyureas
with iodine(III) reagents.[16] Lovick and Michael
67 (6a)
50 (6a)
53 (6a)
[a] Isolated yields are reported using ~0.5 mmol of 5.
demonstrated the cyclization of unsaturated sulfona- Koser’s reagent to 5, led to an increased yield of 68%
mides employing iodine(III) reagents.[17] Wang and co- (entry 8) whereas using just 2 equiv. gave an inferior
workers reported the cyclization of unsaturated oximes 41% (entry 9). We then turned our attention back to the
with Koser’s reagent 7 but an iron(II) catalyst was original substrate (where R1 =H), and subjected it to
required for efficient conversion.[18]
the modified reaction conditions, but only a low yield
We initiated our investigation by attempting to was returned (entry 10). Modifying the carbamate
cyclize methyl allylcarbamates 5a by treatment with oxygen group led to a striking change in yield, with i-
°
3 equiv. of Koser’s reagent 7 in MeCN at 80 C butyl 5c performing somewhat better (entry 11) than
(Table 1, entry 1). Pleasingly, the desired transforma- the methyl 5b but the t-butyl version 5d was
tion took place, but in modest yield. Methylation of the significantly better with 76% yield being obtained with
carbamate nitrogen provided a new substrate 5b which 3 equiv. of Koser’s reagent (entry 12). We also
was subjected to the same conditions for cyclization modified the Koser’s reagent structure and investigated
and a superior yield of oxazolidinone was observed the impact on the yield of oxazolidinone formation.
(entry 2). Lowering the temperature for the cyclization Studying the best performing t-butyl substrate variant
°
to 50 C led to a slight decrease in yield (entry 3). 5d, installing a chloro or fluoro substituent at the 4-
Changing solvent to DCE led to a similar result position of the Koser’s reagent aromatic ring led to a
(entry 4) whereas MeOH provided a complex mixture slight drop in cyclization yield in both cases (entries 13
of compounds (entry 5). Using trifluoroethanol as and 14). Using the Koser’s reagent 10 prepared from
solvent, led to a jump in yield to 48% (entry 6) and 5-iodo-m-xylene led to a jump in yield of cyclization
hexafluoroisopropanol (HFIP) resulted in a yield of to 95% (entry 15). Reducing the amount of modified
59% (entry 7). Increasing the number of equivalents of Koser’s reagent to 2 equiv. led to a slight drop in yield
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(entry 16) whereas using 1.2 equiv. resulted in 65%
yield (entry 17). The Koser’s reagent 11 derived from
2-iodomesitylene proved ineffective at mediating cyc-
lization (entry 18). Koser’s reagents 12, 13 and 14
derived from 1-iodo-4-(trifluoromethyl)benzene, iodo-
pentafluorobenzene and 3-iodoanisole led to moderate
yields of oxazolidinone (entries 19–21).
It was decided that using three equivalents of
oxidant was undesirable for the modest increase in
yield obtained over using two equivalents, therefore
the optimized reaction conditions were taken to be 2
equivalents of 5-iodo-m-xylene derived Koser’s re-
°
agent 10 in HFIP at 50 C. Subsequently, the scope of
the cyclization reaction was explored (Scheme 2). The
nitrogen substituent was changed from hydrogen to
alkyl and to aryl and all examples were successfully
cyclized. The methyl carbamate, rather than the t-butyl
carbamate in 5d, was used in all cases with little to no
drop in yields being observed. Aryl substrates contain-
ing electron-withdrawing or electron-donating groups
such as a nitro, an ester, a nitrile, a methoxy, a
trifluoromethoxy and alkyls were investigated. Poten-
tially oxidizable substrates such as 5q and 5s
containing a pyrazole and an iodoaryl group respec-
tively were successfully cyclized. Further substitution
on the oxazolidinone ring was also found to be
possible with 6t formed in moderate yield, but with
low selectivity. Six-membered ring 6u was prepared in
a similar manner from the homoallyl carbamate.
In order to demonstrate the utility of these com-
pounds, a couple of derivatizations were effected
(Scheme 3). Treatment of 6r with morpholine led to
smooth SN2 displacement of the tosylate to give 15 in
94% yield. Suzuki coupling of 6s with a pyridine
derivative, under unoptimized conditions,[8a] generated
the tosylated analog of tedizolid 16 in moderate yield.
The mechanism of this cyclization process is
proposed to proceed through activation of the alkene
by the modified Koser’s reagent, which induces
cyclization by attack of the carbonyl oxygen
(Scheme 4).[19] Removal of the methyl by the solvent,
or an adventitious tosylate, generates iodonium 17
which undergoes SN2 displacement by tosylate to
furnish the final product. It is envisaged that the acidic
solvent HFIP aids this process.
Next, we turned our attention to the use of chiral
λ3-iodanes in order to effect this transformation in an
enantioselective fashion. We needed to prepare chiral
derivatives of Koser’s reagent; however, most chiral
iodanes reported are diacetates.[13] After some exper-
imentation, we were able to prepare the iodane 18
from the known diacetoxyiodoarene and we added it to
a solution of carbamate 5b (Scheme 5). Pleasingly, the
Scheme 2. Scope of cyclization. Isolated yields are reported
typically using between 0.2 and 0.6 mmol of 6.
oxazolidinone 6b was isolated in an encouraging 62% sented. It was discovered that a modified version of
ee.
Koser’s reagent was necessary in order to obtain high
In conclusion, a hypervalent iodine mediated yields in most cyclisation reactions and that the
approach to oxazolidinone formation has been pre- products can be readily derivatized. Preliminary work
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Acknowledgements
We thank Astrastkal Ltd. and the University of Huddersfield for
funding. We thank Dr Neil McLay for his NMR expertise.
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Experimental Section
Representative procedure for cyclization: tert-butyl allyl
carbamate 5d (0.16 g, 1.0 mmol, 1 equiv) and (3,5-dimethyl-
phenyl)(hydroxy)-λ3-iodaneyl 4-methylbenzenesulfonate 10
(1.26 g, 3.0 mmol, 3 equiv) were dissolved in HFIP (10 mL).
°
The mixture was heated at 50 C for 16 hours, then cooled and
concentrated under vacuum. The residue was diluted with ethyl
acetate (10 mL) and passed through a 2 cm plug of silica gel.
The crude product was purified by flash chromatography (silica
gel; 3:7 petroleum ether/EtOAc) and 6a was isolated as a white
solid (0.26 g, 97%). HFIP is 1,1,1,3,3,3-hexafluoroisopropanol.
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