Substrate scope and stereocontrol in the Rh(II)-catalysed oxyamination of allylic carbamates

Article abstract of DOI:10.1016/j.tet.2014.06.051

Application of a modified Du Bois protocol for rhodium-stabilised nitrenoid generation to a variety of allylic carbamates results in 4-acetoxymethyl-1,3-oxazolidin-2-one derivatives with moderate to high levels of stereocontrol.

Full text of DOI:10.1016/j.tet.2014.06.051

Tetrahedron 70 (2014) 7388e7394
Contents lists available at ScienceDirect
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Substrate scope and stereocontrol in the Rh(II)-catalysed
oxyamination of allylic carbamates
,
,
William P. Unsworth a y, Scott G. Lamont b, Jeremy Robertson a
*
a Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK
b AstraZeneca Global R&D, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Application of a modified Du Bois protocol for rhodium-stabilised nitrenoid generation to a variety of
allylic carbamates results in 4-acetoxymethyl-1,3-oxazolidin-2-one derivatives with moderate to high
levels of stereocontrol.
Received 20 May 2014
Accepted 13 June 2014
Available online 24 June 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Aminohydroxylation
Aziridination
Rhodium(II) catalysis
Stereoselective
Oxazolidinones
1. Introduction
Exploratory work concerning the stereoselective synthesis of
biologically active aminopolyols led us to evaluate tethered ami-
nohydroxylation (TA)1 and related processes from dienyl carba-
mates and sulfamates. Thus, with 1,2-dienyl (allenyl) substrates,
iminocyclopropane adducts were obtained from sulfamates2 and
bicyclic methylene aziridines from carbamates.3 In a second line of
investigation, the novel 1,4-dienyl carbamate 1 (Scheme 1),4 pre-
pared from divinyl carbinol using the standard procedure,5 was
subjected to the published TA conditions to give oxazolidinone 2
(79:21 trans/cis ratio) in 65% unoptimised yield.6 The dr was raised
to 96:4 by Pd(0)-mediated equilibration7 and pure trans-2 was
obtained by recrystallisation from ethyl acetate. This versatile in-
termediate was then applied in an approach to the glycosidase
inhibitor nagstatin6 and a concise synthesis of (ꢀ)-safingol.4
With the intention of developing alternatives to the published
route to (R,R)- and (S,S)-2 from serine enantiomers,8 and consid-
ering that an asymmetric TA variant was not available, we consid-
ered a related intramolecular aziridination/ring-opening process
(Scheme 2). This was expected to offer opportunities for controlling
the absolute stereochemistry and, in broader applications, would
Scheme 1.
Scheme 2.
provide an overall anti-1,2-aminohydroxylation of the alkene in
contrast to the syn-stereospecific TA. Intramolecular aziridination
by thermal or photochemical loss of nitrogen from azidoformates9
was discounted on the basis of limited prospects for achieving
asymmetric variants. This left a choice between sulfamates10 and
carbamates11 as aziridination precursors, from which nitrenoid
reactive intermediates may be generated by oxidation, usually with
* Corresponding author. Tel.: þ44 1865 275660; e-mail address: jeremy.rob-
ertson@chem.ox.ac.uk (J. Robertson).
y
Current address: Department of Chemistry, University of York, Heslington, York
YO10 5DD, UK.
http://dx.doi.org/10.1016/j.tet.2014.06.051
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

W.P. Unsworth et al. / Tetrahedron 70 (2014) 7388e7394
7389
an iodine(III) reagent, and complexation, for example, with a rho-
dium(II) or copper(I) catalyst.12 Finally, because allylic sulfamates
are relatively unstable, we focused on carbamate substrates (Y¼C in
Scheme 2).
Application of Du Bois’ original conditions for CH-insertion re-
actions13 [PhI(OAc)2, Rh2(OAc)4 or Rh2(TPA)4, MgO, CH2Cl2, 40 ꢁC]
to alkene aziridination delivers either intact aziridines, or products
of ring-opening by acetate liberated from the I(III) oxidant.11,14 The
balance seems to be a fine one with glycal- and indole-derived
aziridines opening readily (SN1-like), with carbocyclic alkene-
derived aziridines requiring higher temperatures. The aziridine is
retained in oxazolidinone-fused products when prepared by Lebel’s
N-sulfonyloxycarbamate modification that requires no external
oxidant,15 and in oxazinanone-fused products generated from
homoallylic carbamates using PhIO as the oxidant.11f The recently-
reported Fe(II)-mediated transformation of allylic N-acylox-
ycarbamates into 4-(acyloxyalkyl)oxazolidinones may also yield
intact aziridines when the reaction is performed at 0 ꢁC;16 this
reaction shows promising enantioselectivity in selected cases but is
not stereospecific.
Scheme 4.
Table 1
Oxyamination outcomes according to Scheme 4
Entry
Carbamate (dr)a
Major product (dr)a
Yield %
1
75
In light of this extensive background, it was surprising that
a systematic study of Du Bois-type aziridination, coupled with ring-
opening in situ by acetate present in the reaction mixture, had not
been reported and, to the best of our knowledge, this is still the
case. Given the potential application of this method in the synthesis
of aminoalcohols we set out to establish whether the reaction is
stereospecific or usefully stereoselective, and whether the appli-
cation of known chiral Rh(II) catalysts would provide acceptable
enantiomeric enrichment. The results of this study are presented
herein.
2
3
62
64
4
5
6
7
8
61
48
46
60
46
2. Results and discussion
As mentioned, prior to this study, the precedent for acetox-
yamination via an allylic carbamate was confined to the reactions of
electron-rich glycal or indole substrates in which the acetolysis
follows a stepwise elimination/addition pathway. Thus, we selected
a range of simple alkenyl substrates that would reveal the inherent
diastereoselectivity and regioselectivity of the process. Precursor
alcohols were either commercially available or, in the case of (Z)-
1,2-disubstituted(alkenyl) alcohols, prepared by standard literature
procedures. For example, Lindlar catalysed partial hydrogenation of
propargyl alcohols, obtained via a CoreyeFuchs sequence from the
appropriate aldehydes,17 gave the corresponding alkenols (Scheme
3). In our hands the hydrogenations were not reliably stereo-
selective and Z/E mixtures were obtained in most cases. For the
purposes of this investigation the levels of enrichment in the Z-
isomer were deemed sufficient.
Scheme 3. Reagents and conditions: (a) CBr4, PPh3, CH2Cl2, 0 ꢁC; (b) BuLi, THF, ꢂ78 ꢁ
C
then (HCHO)n, THF, ꢂ78 ꢁC to rt; (c) Cl3CCONCO, CH2Cl2, 0 ꢁC then K2CO3, aq MeOH; (d)
H2, Lindlar’s catalyst, quinoline, MeOH.
9
53
75
With these substrates (3aeo, 1), a slight modification to the
original Du Bois conditionsdincreasing the temperature to 50 ꢁC
and using the more organic soluble Rh2(oct)4 in place of
Rh2(OAc)4dresulted in all cases in the formation of 4-(acetox-
ymethyl)oxazolidinones 4aep (Scheme 4 and Table 1). Apart from
oxazolidinone 4a18 (entry 1), all products are novel compounds and
10
(continued on next page)

7390
W.P. Unsworth et al. / Tetrahedron 70 (2014) 7388e7394
Table 1 (continued )
essentially as single diastereoisomers; the methyl (3f) and the
Carbamate (dr)a
Major product (dr)a
Yield %
69
branched alkyl substrates 3h and 3i proceeded with a small
erosion in dr.
Entry
(d) The stereospecificity arises formally by concerted aziridination,
and SN2-like acetolysis of the exo-CeN bond. This was sup-
ported initially by comparison of the reactions of E-3c and Z-3f,
which provided opposite major:minor diastereomeric products
4c and 4f, respectively. Confirmation of the stereochemistry of
4g was obtained by effecting partial hydrolysis of the acetate
with aq NaOH in THF to give alcohol 5 (Scheme 5) with the
NMR data matching those published.1e The reaction had to be
quenched prior to completion in order to limit competing acyl
transfer; with aq LiOH and a longer reaction time, complete
conversion to regioisomer 619 resulted.
11
12
13
14
15
64
56
60
50
Scheme 5. Reagents and conditions: (a) NaOH, aq THF, 4 h; (b) LiOH, aq THF, 23 h.
(e) Further substitution at the alkene terminus (substrates 3l and
3m) or at the carbamate a-position (3n) is well-tolerated, with
the reaction of neryl carbamate 3m affording essentially a sin-
gle diastereoisomer. It was disappointing that the reaction of
our original pentadienyl carbamate (1, entry 16) showed no
apparent facial bias during the aziridination, leading to a 1:1
mixture of cis- and trans-oxazolidinones 4p.
16
46
a
Diastereomeric ratios refer to major : minor as judged by comparisons of in-
tegral values in the 1H NMR spectra; only the major isomers are depicted and where
a dr is not given, essentially a single diastereomer was observed. For 4aep, the
quoted dr in each case refers to that present in the crude product mixture.
(f) The results from substrates 3d and 3o are noteworthy because
the yields reported for the analogous TA reactions are 41% for
3d1a and for 3o the reaction failed completely.1b
We briefly explored the possibility of effecting the reaction in
the presence of added nucleophiles that may out-compete acetate
for aziridine ring-opening. The addition of 1.0 mol equivalent of
methanol in the reaction of prenyl carbamate (3l) had little effect,
the obtained oxazolidinone consisting entirely of the acetox-
ymethyl derivative 4l; using a five-fold excess of methanol returned
a roughly 1:1 mixture of methoxy- (7, Fig. 1) and acetoxy- (4l)
products. With the same substrate (3l), and 5.0 equiv of water, the
reaction was largely suppressed and only a 20% conversion, to the
acetoxy-product 4l, resulted. The addition of 5.0 equiv of diethyl-
amine or 5.0 equiv of sodium azide led to the complete recovery of
starting material. However, results with substrates such as alcohol
8 bearing an internal nucleophile, specifically a 3-hydroxypropyl-
substituent, led to bicyclic products of the form 9; these will be
reported separately.20
the relative stereochemistry was confirmed in selected cases, see
below.
From the table, several key points emerge:
(a) Oxazolidinones 4aep are formed with excellent conversion,
and the yields are comparable to those reported for indole and
glycal substrates.
(b) Acetolysis of the intermediate aziridines is completely regio-
selective, proceeding via cleavage of the exo-CeN bond to form
oxazolidinones (cf. Scheme 2) rather than via endo-CeN
cleavage and oxazinanone formation. This is the normal ring-
opening mode for carbamate-derived bicyclic aziridines, ex-
pected on the basis of effective delocalisation of the CeN
bonding electrons into the roughly parallel C]O
p-system as
the addition progresses.
(c) The reactions retain most but by no means all of the stereo-
chemical integrity (E/Z) of the precursors. For example, the
reaction of the sorbyl substrate 3d proceeds with a high degree
of stereospecificity, but the E-crotyl substrate 3c suffers an
erosion in dr during the aziridination and acetolysis from 16:1
to 10:1. The situation is more pronounced in the cinnamyl ex-
ample 3e where an erosion of the dr may more easily arise from
an SN1-like acetolysis. In the Z-1,2-disubstituted cases, the
unbranched alkyl substrates 3g, 3j, and 3k gave products
Fig. 1. Products arising from inter- (7) and intra-molecular (9, from substrate 8)
alkoxyamination.

W.P. Unsworth et al. / Tetrahedron 70 (2014) 7388e7394
7391
3. Conclusion
evaporated and the remaining aqueous residue extracted with
dichloromethane (3ꢃ20 mL). The combined organic extracts were
concentrated in vacuo and purified by column chromatography
(petrol/ethyl acetate, 4:1) to give the carbamates (1, 3aeo). As an
alternative work-up, the crude reaction mixture was loaded onto
a pad of basic alumina and allowed to stand for 5 min before
flushing through with ethyl acetate and concentrating in vacuo.
An operationally simple and reliable procedure for the acetox-
yamination of a broad range of allylic carbamates has been estab-
lished. These reactions result in the formation of two contiguous
stereocentres from readily available starting materials, and proceed
with high diastereocontrol and complete regiocontrol. The oppor-
tunity to develop asymmetric variants of these procedures, using
any of the increasing number of known chiral dirhodium cata-
lysts,21 enhances the value of this methodology and is an obvious
objective for future work in this field.22
4.3. Penta-1,4-dien-3-yl carbamate (1)6
White solid (4.84 g, 86%). Rf 0.55 (ethyl acetate); mp 40e42 ꢁC;
nmax (thin film)/cmꢂ1 3432s, 3274m, 3214m, 1688s, 1614s, 1410s,
1289w; dH (400 MHz, CDCl3) 4.72 (2H, br s, NH2), 5.22 (2H, d, J
10.4 Hz) and 5.30 (2H, d, J 17.2 Hz, 2ꢃ ]CH2), 5.57e5.60 (1H, m,
OCH), 5.84 (2H, ddd, J 17.2, 10.4, 5.8 Hz, 2ꢃ CH]CH2); dC (100 MHz,
CDCl3) 75.6 (CH), 117.2 (CH2), 135.3 (CH), 156.3 (C); HRMS (CIþ)
found 128.0713, C6H10NO2 (MHþ) requires 128.0712.
4. Experimental section
4.1. General aspects
Commercially available reagents were dried and purified before
use where appropriate using standard procedures. ‘Petrol’ refers to
the fraction of petroleum ether boiling in the range 30e40 ꢁC; ether
refers to diethyl ether; methanol and dichloromethane were dried
by passing through activated alumina under argon. All other sol-
vents and reagents were used as supplied without prior purifica-
tion. Reactions were routinely carried out in oven-dried glassware
under an argon atmosphere. Diastereomeric ratios (dr) were cal-
culated from the integration of 1H NMR resonances. Thin layer
chromatography was performed using Merck aluminium-backed
0.2 mm Kieselgel 60 F254 pre-coated plates. Plates were visualised
by the quenching of ultraviolet fluorescence (lmax 254 nm) then
stained and heated with either anisaldehyde or potassium per-
manganate. Retention factors (Rf) are reported with the solvent
system used in parentheses. Flash column chromatography was
4.4. (Z)-But-2-enyl carbamate (3f)
White solid (77 mg, 82%), a mixture of geometrical isomers (Z/E,
5:1). Rf 0.70 (ethyl acetate); mp 40e42 ꢁC; nmax (thin film)/cmꢂ1
3352br, 3030w, 2946w, 1714s, 1602m, 1394w, 1322s, 1057m, 785w;
dH (400 MHz, CDCl3) Data for the Z-isomer: 1.70 (3H, d, J 7.0 Hz,
CH3), 4.63 (2H, d, J 6.8 Hz, OCH2), 4.80 (2H, br s, NH2), 5.52e5.59
(1H, m, CH2CH), 5.68e5.75 (1H, m, CHCH3); dC (100 MHz, CDCl3)
13.1 (CH3), 60.7 (CH2),124.5 (CH),129.5 (CH),157.6 (C); HRMS (ESIþ)
found 138.0535, C5H9NNaO2 (MNaþ) requires 138.0525.
4.5. (Z)-4-Methylpent-2-enyl carbamate (3h)
performed on Merck 60 silica with a particle size of 40e63 mm; the
solvent system is given in parentheses. Melting points were de-
termined using a Griffin heated metal block apparatus and are
uncorrected. Infrared spectra were recorded as thin films on NaCl
disks using a PerkineElmer Paragon 1000 FT-IR spectrophotometer
or a Bruker Tensor 27 FT-IR. Absorption maxima (nmax) are given in
wavenumbers (cmꢂ1) and are classified as strong (s), medium (m),
weak (w) and broad (br). Proton (1H) NMR spectra were recorded
on the following spectrometers: Bruker AVC-500 (500 MHz);
Bruker DQX-400 or DPX-400 (400 MHz); Bruker DPX-200
(200 MHz). Assignments were made on the basis of chemical
shift and coupling constants using COSY and NOE experiments
where appropriate. Abbreviations used in the description of mul-
tiplicities are singlet (s), doublet (d), triplet (t), quartet (q), quintet
(quin), sextet (sext), multiplet (m), apparent (app) and broad (br).
Coupling constants (J) are quoted to the nearest 0.1 Hz. Carbon-13
White solid (from partial hydrogenation of the corresponding
propargylic carbamate); a fraction of dr¼20:1, obtained by chro-
matography on AgNO3-impregnated silica, was used for charac-
terisation. Rf 0.67 (ethyl acetate); mp 38e40 ꢁC; nmax (thin film)/
cmꢂ1 3411br, 3026w, 2956m, 1683s, 1486m, 1121m, 801w, 725w; dH
(500 MHz, CDCl3) 0.96 (6H, d, J 6.6 Hz, 2ꢃ CH3), 2.61e2.70 (1H, m,
CH(CH3)2), 4.62 (2H, d, J 6.0 Hz, OCH2), 4.73 (2H, br s, NH2),
5.39e5.50 (2H, m, CH]CH); dC (125 MHz, CDCl3) 23.0 (CH3), 27.0
(CH), 61.1 (CH2), 121.1 (CH), 142.6 (CH), 156.9 (C); HRMS (CIþ) found
143.0939, C7H13NO2 (MHþ) requires 143.0946.
4.6. (Z)-4,4-Dimethylpent-2-enyl carbamate (3i)
Colourless oil (52 mg, 51%), a mixture of geometrical isomers (Z/
E, 5:1). Rf 0.56 (ethyl acetate); nmax (thin film)/cmꢂ1 3347br, 1716s,
1379w, 1324m, 1055m; dH (500 MHz, CDCl3) 1.13 (9H, s, C(CH3)3),
4.60 (2H, br s, NH2), 4.78 (2H, d, J 6.4 Hz, OCH2), 5.31 (1H, dt, J 12.3,
6.4 Hz, CH2CH), 5.53 (1H, d, J 12.3 Hz, CHC(CH3)3); dC (125 MHz,
CDCl3) 30.8 (CH3), 33.6 (C), 61.8 (CH2), 122.3 (CH), 143.9 (CH), 156.6
(C); HRMS (ESIþ) found 180.0992, C8H15NNaO2 (MNaþ) requires
180.0995.
(
13C) NMR spectra were recorded on the following spectrometers:
Bruker AVC-500 (125 MHz); Bruker DQX-400 or DPX-400
(100 MHz). Assignments were made on the basis of DEPT, HMBC
and HSQC experiments as appropriate. High resolution mass
spectra (HRMS) were recorded using a Micromass GCT (CI),
a Micromass AutoSpec-oaTOF (CI or EI), or a Micromass LCT (ESI).
Mass to charge ratios (m/z) are reported in Daltons. Known carba-
mates 3aee, 3g, 3l, and 3m were prepared by the standard pro-
cedure from the corresponding alcohol.5
4.7. (Z)-Non-2-enyl carbamate (3j)
4.2. General procedure for synthesis of oxyamination
substrates
Colourless oil (1.19 g, 91%). Rf 0.66 (ethyl acetate); nmax (thin
film)/ cmꢂ1 3350br, 2928s, 2856w, 1713s, 1601w, 1458w, 1387m,
1328m, 1053m, 784w; dH (400 MHz, CDCl3) 0.87 (3H, t, J 6.4 Hz,
CH3), 1.21e1.37 (8H, m, C4H8CH3), 2.08 (2H, app q, J 7.0 Hz, ]
CHCH2), 4.60 (2H, d, J 6.8 Hz, OCH2), 4.99 (2H, br s, NH2), 5.47e5.55
(1H, m, OCH2CH]), 5.58e5.66 (1H, m, ]CHCH2); dC (100 MHz,
CDCl3); 14.0 (CH3), 22.6 (CH2), 27.5 (CH2), 28.8 (CH2), 29.4 (CH2),
31.6 (CH2), 61.0 (CH2), 123.5 (CH), 135.3 (CH), 157.2 (C); HRMS (ESIþ)
found 208.1309, C10H19NNaO2 (MNaþ) requires 208.1308.
Trichloroacetyl isocyanate (1.0 mL, 8.46 mmol) was added
dropwise to a stirred solution of the alcohol (7.05 mmol) in dry
dichloromethane (15.0 mL) at 0 ꢁC. After stirring for 1 h the mixture
was concentrated in vacuo, dissolved in methanol (20 mL) and
cooled to 0 ꢁC. K2CO3 solution (aq, 2.0 M, 10 mL) was added, and the
mixture was warmed to RT then stirred for 3 h. The methanol was

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W.P. Unsworth et al. / Tetrahedron 70 (2014) 7388e7394
4.8. (Z)-4-(tert-Butyldimethylsilyloxy)but-2-enyl carbamate
(3k)
(CH2) 70.4 (CH), 160.0 (C), 170.4 (C); HRMS (ESIþ) found 196.0579,
C7H11NNaO4 (MNaþ) requires 196.0580.
Pale yellow oil (606 mg, 52%); nmax (thin film)/cmꢂ1 3355br,
2930m, 2850w, 1717s, 1603w, 1390m, 1319m, 1256w, 1065s, 838m,
778w; dH (400 MHz, CDCl3) 0.08 (6H, s, Si(CH3)2), 0.90 (9H, s,
C(CH3)3), 4.64 (2H, d, J 5.8 Hz) and 4.74 (2H, d, J 6.6 Hz, 2ꢃ OCH2),
4.74 (2H, br s, NH2), 5.53e5.62 (1H, m) and 5.70e5.77 (1H, m, CH]
CH); dC (100 MHz, CDCl3) ꢂ5.2 (CH3), 18.3 (C), 25.9 (CH3), 59.5
(CH2), 61.0 (CH2), 124.3 (CH), 133.3 (CH), 156.6 (C); HRMS (ESIþ)
found 268.1339, C11H23NNaO3Si (MNaþ) requires 268.1339.
4.14. (S*,E)-1-[(R*)-2-Oxooxazolidin-4-yl]but-2-enyl acetate
(4d)
Colourless oil (61 mg, 61%) from carbamate 3d. Rf 0.40 (ethyl
acetate); nmax (thin film)/cmꢂ1 3290br, 2920w, 1746s, 1409w,
1374m,1232s,1026m, 969w, 768w; dH (400 MHz, CDCl3) 1.74 (3H, d,
J 6.6 Hz, CH3), 2.08 (3H, s, COCH3), 4.00 (1H, app dt, J 8.9, 4.9 Hz,
CHNH), 4.22 (1H, ddd, J 8.9, 4.9, 1.2 Hz) and 4.42 (1H, app td, J 8.9,
1.2 Hz, OCH2), 5.20e5.25 (1H, m, CHOAc), 5.33e5.41 (1H, m,
CHCH]), 5.85e5.94 (1H, m, CHCH3), 6.05e6.20 (1H, m, NH); dC
(100 MHz, CDCl3) 18.0 (CH3), 21.0 (CH3), 54.6 (CH), 66.1 (CH2), 74.7
(CH), 123.5 (CH), 133.9 (CH), 159.6 (C), 170.0 (C); HRMS (ESIþ) found
222.0738, C9H13NNaO4 (MNaþ) requires 222.0737.
4.9. 2-Methylbut-3-en-2-yl carbamate (3n)
White solid (302 mg, 83%). Rf 0.62 (ethyl acetate); mp 56e58 ꢁC;
nmax (KBr)/cmꢂ1 3458m, 2360w, 1686s, 1603w, 1379m, 1133m,
1036w; dH (400 MHz, CDCl3) 1.53 (6H, s, 2ꢃ CH3), 4.59 (2H, br s,
NH2), 5.08 (1H, dd, J 10.9, 0.7 Hz) and 5.17 (1H, dd, J 17.5, 0.7 Hz, ]
CH2), 6.12 (1H, dd, J 17.5, 10.9 Hz, CH]); dC (100 MHz, CDCl3) 26.7
(CH3), 80.1 (C),112.4 (CH2),142.9 (CH),155.9 (C); HRMS (ESIþ) found
152.0681, C6H11NNaO2 (MNaþ) requires 152.0682.
4.15. (S*)- and (R*)-[(R*)-2-Oxooxazolidin-4-yl](phenyl)
methyl acetate (4e)
Colourless viscous oil (57 mg, 48%) from carbamate 3e, a mix-
ture of diastereoisomers (A:B¼63:37). Rf 0.31 (ethyl acetate); nmax
(thin film)/cmꢂ1 3285br, 1754s, 1408w, 1374w, 1231m, 1037m,
922w, 703w; dH (400 MHz, CDCl3) 2.13 (3H, s, COCH3, B), 2.15 (3H, s,
COCH3, A) 4.06e4.10 (1H, m, NCH, B), 4.17e4.40 (5H, m, OCH2, A & B,
NCH, A), 5.68 (1H, d J 7.5 Hz, CHPh, B), 5.82 (1H, d, J 5.7 Hz, CHPh, A),
5.83 (1H, br s, NH, A), 6.67 (1H, br s, NH, B), 7.31e7.42 (10H, m, Ph, A
& B); dC (100 MHz, CDCl3) 21.0 (CH3, B), 21.0 (CH3, A), 56.0 (CH, A),
56.2 (CH, B), 66.2 (CH2, B), 66.3 (CH2, A), 75.2 (CH, A), 77.1 (CH, B),
126.6 (CH, A), 127.1 (CH, B), 129.0 (two peaks), 129.1 and 129.2 (CH),
135.4 (C, A), 135.5 (C, B), 159.2 (C, A), 159.6 (C, B), 169.9 (C, A), 170.0
(C, B); HRMS (ESIþ) found 258.0740, C12H13NNaO4 (MNaþ) requires
258.0737.
4.10. General procedure for intramolecular oxyamination
A solution of the O-allyl carbamate (1, 3aeo; 0.50 mmol) in
dichloromethane (3.0 mL) was placed in a sealable pressure vessel
and the headspace was purged with argon. MgO (56.0 mg,
1.66 mmol), diacetoxyiodobenzene (280 mg, 0.84 mmol), and
rhodium(II) octanoate dimer (19.5 mg, 0.025 mmol) were added
sequentially under a flow of argon. The reaction mixture was stirred
vigorously at 50 ꢁC for 18 h. The solution was cooled, the solvent
was removed in vacuo, and the resulting solid residue was purified
by column chromatography through a short plug of silica (pet-
rol/petrol/ethyl acetate, 3:1/petrol/ethyl acetate, 1:1) giving
oxazolidinones 4aep.
4.16. (R*)-1-[(R*)-2-Oxooxazolidin-4-yl]ethyl acetate (4f)
4.11. (2-Oxooxazolidin-4-yl)methyl acetate (4a)18
Pale yellow viscous oil (11 mg, 46%) from carbamate 3f, with
dr¼3:1 in the crude product. Rf 0.22 (ethyl acetate); dH (400 MHz,
CDCl3) 1.24 (3H, d, J 6.3 Hz, CH3), 2.10 (3H, s, COCH3), 3.90e3.95 (1H,
m, NCH), 4.17 (1H, dd, J 9.0, 5.2 Hz) and 4.48 (1H, app t, J 9.0 Hz,
OCH2), 4.86e4.92 (1H, m, CHCH3), 5.77 (1H, br s, NH); dC (100 MHz,
CDCl3) 15.6 (CH3), 20.8 (CH3), 55.7 (CH), 66.5 (CH2), 71.1 (CH), 160.0
(C), 170.4 (C); HRMS (ESIþ) found 196.0579, C7H11NNaO4 (MNaþ)
requires 196.0580.
Colourless oil (59 mg, 75%) from carbamate 3a. Rf 0.13 (ethyl
acetate); nmax (thin film)/cmꢂ1 3301br, 1740s, 1413w, 1235m,
1045m, 936w, 770w; dH (400 MHz, CDCl3) 2.10 (CH3), 4.03e4.20
(4H, m, OCH2CHCHH0) 4.50 (1H, app t, J 8.5 Hz, OCH2CHCHH0), 6.55
(1H, br s, NH); dC (100 MHz, CDCl3); 20.6 (CH3), 51.1 (CH), 64.9
(CH2), 66.9 (CH2), 159.8 (C), 170.8 (C) [lit.18 20.7, 51.1, 64.9, 66.9,
159.8, 170.8].
4.17. (R*)-1-[(R*)-2-Oxooxazolidin-4-yl]butyl acetate (4g)
4.12. (4-Methyl-2-oxooxazolidin-4-yl)methyl acetate (4b)
Colourless oil (120 mg, 60%) from carbamate 3g. Rf 0.42 (ethyl
acetate); nmax (thin film)/cmꢂ1 3279br, 2962m, 1743s, 1413w,
1375w, 1234s, 1028m, 919w, 732w; dH (400 MHz, CDCl3) 0.91 (3H, t,
J 7.3 Hz, CH2CH3), 1.23e1.60 (4H, m, C2H4), 2.10 (3H, s, COCH3), 3.95
(1H, app dt, J 8.8, 5.2 Hz, CHNH), 4.14 (1H, dd, J 8.8, 5.2 Hz) and 4.43
(1H, app t, J 8.8 Hz, OCH2), 4.92e4.96 (1H, m, CHOAc), 7.11 (1H, br s,
NH); dC (100 MHz, CDCl3) 13.8 (CH3), 18.4 (CH2), 20.9 (CH3), 32.4
(CH2), 54.9 (CH), 66.8 (CH2), 73.7 (CH), 160.3 (C), 170.9 (C); HRMS
(ESIþ) found 224.0884, C9H15NNaO4 (MNaþ) requires 224.0893.
Colourless oil (27 mg, 62%) from carbamate 3b. Rf 0.28 (ethyl
acetate); nmax (thin film)/cmꢂ1 3288br, 1743s, 1381w, 1237m,
1046m; dH (400 MHz, CDCl3) 1.39 (3H, s, CCH3), 2.12 (3H, s, COCH3),
3.98 (1H, d, J 11.5 Hz, CHH0OAc), 4.07 (1H, d, J 8.8 Hz, OCHH0), 4.13
(1H, d, J 11.5 Hz, CHH0OAc), 4.29 (1H, d, J 8.8 Hz, OCHH0), 6.04 (1H, br
s, NH); dC (100 MHz, CDCl3) 20.7 (CH3), 23.0 (CH3), 57.1 (C), 68.1
(CH2), 73.0 (CH2), 158.8 (C), 170.7 (C); HRMS (ESIþ) found 196.0573,
C7H11NNaO4 (MNaþ) requires 196.0580.
4.13. (S*)-1-[(R*)-2-Oxooxazolidin-4-yl]ethyl acetate (4c)
4.18. (R*)-2-Methyl-1-[(R*)-2-oxooxazolidin-4-yl]propyl ace-
tate (4h)
Pale yellow viscous oil (66 mg, 64%) from carbamate 3c, with the
same dr (10:1) as the crude product. Rf 0.22 (ethyl acetate); nmax
(thin film)/cmꢂ1 3288br, 1741s, 1413w, 1376w, 1239s, 1069m, 929w,
769w; dH (400 MHz, CDCl3) 1.25 (3H, d, J 6.5 Hz, CHCH3), 2.08 (3H, s,
COCH3), 3.94e3.99 (1H, m, NCH), 4.26 (1H, dd, J 8.9, 5.0 Hz) and
4.47 (1H, app t, J 8.9 Hz, OCH2), 4.95e5.02 (1H, m, CHCH3), 6.58 (1H,
br s, NH); dC (100 MHz, CDCl3) 15.1 (CH3), 21.0 (CH3), 55.5 (CH), 66.2
Colourless oil (21 mg, 46%) from carbamate 3h, with dr¼2.5:1 in
the crude product from which a sample with dr>10:1 was obtained
for characterisation. Rf 0.42 (ethyl acetate); nmax (thin film)/ cmꢂ1
3274br, 1748s, 1374w, 1237s, 1026m, 768w; dH (500 MHz, CDCl3)
0.93 (3H, d, J 6.6 Hz, CH3), 0.97 (3H, d, J 6.8 Hz, CH3), 1.82e1.89 (1H,
m, CH(CH3)2), 2.15 (3H, s, COCH3), 4.09e4.14 (2H, m, CHNH, OCHH0),

W.P. Unsworth et al. / Tetrahedron 70 (2014) 7388e7394
7393
4.43e4.49 (1H, m, OCHH0), 4.76e4.79 (1H, m, CHOAc), 6.22 (1H, br
s, NH); dC (125 MHz, CDCl3) 17.9 (CH3), 18.9 (CH3) 20.7 (CH3), 29.3
(CH), 53.1 (CH), 67.2 (CH2), 78.0 (CH), 159.8 (C), 171.0 (C); HRMS
(ESIþ) found 224.0894, C9H15NNaO4 (MNaþ) requires 224.0893.
1.58 (3H, s, CH3), 1.66 (3H, s, CH3), 1.81e1.85 and 1.93e2.01 (4H, m,
C2H4), 2.03 (3H, s, COCH3), 4.11e4.19 (1H, m, OCHH0), 4.35e4.42
(2H, m, OCHH0, NHCH), 5.04 (1H, t, J 6.9 Hz, ]CH), 6.88 (1H, br s,
NH); dC (100 MHz, CDCl3) 17.6 (CH3), 18.4 (CH3), 21.8 (CH2), 22.1
(CH3), 25.6 (CH3), 34.2 (CH2), 57.4 (CH), 65.7 (CH2), 84.4 (CH), 122.9
(CH), 132.6 (C), 160.1 (C), 170.4 (C); HRMS (ESIþ) found 278.1359,
4.19. (R*)-2,2-Dimethyl-1-[(R*)-2-oxooxazolidin-4-yl]propyl
acetate (4i)
C
13H21NNaO4 (MNaþ) requires 278.1363.
Colourless oil (13 mg, 53%) from carbamate 3i, with dr¼3.5:1 in
the crude product from which a sample with dr>10:1 was obtained
for characterisation. Rf 0.44 (ethyl acetate); nmax (thin film)/cmꢂ1
3282br, 2963m,1761s,1372w,1236s,1157w,1051m, 913w, 809w; dH
(500 MHz, CDCl3) 0.96 (9H, s, C(CH3)3), 2.16 (3H, s, COCH3),
4.12e4.19 (2H, m, CHNH, OCHH0), 4.48 (1H, app t, J 7.7 Hz, OCHH0),
4.75 (1H, d, J 3.6 Hz, CHOAc), 5.68 (1H, br s, NH); dC (125 MHz,
CDCl3) 20.7 (CH3), 29.3 (CH3), 34.1(C), 52.0 (CH), 68.8 (CH2), 79.6
(CH), 159.5 (C), 170.8 (C); HRMS (ESIþ) found 238.1051,
4.24. (5,5-Dimethyl-2-oxooxazolidin-4-yl)methyl acetate (4n)
Colourless oil (56 mg, 60%) from carbamate 3n. Rf 0.42 (ethyl
acetate); nmax (thin film)/cmꢂ1 3300br, 2982w, 1745s, 1375w,
1230m, 1044w; dH (400 MHz, CDCl3) 1.41 (3H, s, CH3), 1.51 (3H, s,
CH3), 2.10 (3H, s, COCH3), 3.71 (1H, dd, J 7.9, 4.5 Hz, CHNH), 4.04 (1H,
dd, J 11.3, 7.9 Hz) and 4.23 (1H, dd, J 11.3, 4.5 Hz, CH2OAc), 6.29 (1H,
br s, NH); dC (100 MHz, CDCl3) 20.7 (CH3), 21.7 (CH3), 28.0 (CH3),
59.7 (CH), 63.3 (CH2), 82.1 (C), 158.3 (C), 170.5 (C); HRMS (ESIþ)
found 210.0728, C8H13NNaO4 (MNaþ) requires 210.0737.
C
10H17NNaO4 (MNaþ) requires 238.1050.
4.20. (R*)-1-[(R*)-2-Oxooxazolidin-4-yl]heptyl acetate (4j)
4.25. (3aS*,4R*,6aR*)-2-Oxo-hexahydro-2H-cyclopenta[d]ox-
azol-4-yl acetate (4o)
Colourless oil (91 mg, 75%) from carbamate 3j, with dr¼10:1 in
the crude product from which a sample with dr¼11:1 was obtained
for characterisation. Rf 0.32 (ethyl acetate); nmax (thin film)/cmꢂ1
3274br, 1758s, 1412w, 1375m, 1236s, 1035m, 934w, 768w, 720w; dH
(400 MHz, CDCl3) 0.82e0.90 (3H, m, CH3), 1.19e1.35 (8H, m,
C4H8CH3), 1.42e1.60 (2H, m, CH2C5H11), 2.11 (3H, s, COCH3),
3.92e4.00 (1H, m, NCH), 4.13 (1H, dd, J 8.8, 5.0 Hz) and 4.43 (1H,
app t, J 8.8 Hz, OCH2), 4.93 (1H, td, J 9.3, 1.2 Hz, CHOAc), 7.01 (1H, br
s, NH); dC (100 MHz, CDCl3) 14.0 (CH3), 20.9 (CH3), 22.5 (CH2), 25.0
(CH2), 29.0 (CH2), 30.3 (CH2), 31.6 (CH2), 54.9 (CH), 66.8 (CH2), 74.0
(CH), 160.2 (C), 170.9 (C); HRMS (ESIþ) found 266.1352,
Colourless oil (29 mg, 50%) from carbamate 3o. Rf 0.41 (ethyl
acetate); nmax (thin film)/cmꢂ1 3300br, 1747s,1375w, 1241m,1169w,
1024m, 936w, 768w; dH (500 MHz, CDCl3) 1.88e1.94 (1H, m,
CH2CHH0), 2.06 (3H, s, COCH3), 2.06e2.13 (3H, m, CH2CHH0), 4.04
(1H, app d, J 7.3 Hz, CHNH), 4.91 (1H, br s, CHOCO$N), 5.13 (1H, app
dd, J 7.3, 5.6 Hz, CHOAc), 5.63 (1H, br s, NH); dC (125 MHz, CDCl3)
21.0 (CH3), 27.9 (CH2), 31.0 (CH2), 62.1 (CH), 79.6 (CH), 81.2 (CH),
158.6 (C), 170.5 (C); HRMS (ESIþ) found 208.0581, C8H11NNaO4
(MNaþ) requires 208.0580.
C
12H21NNaO4 (MNaþ) requires 266.1363.
4.26. cis- and trans-(2-Oxo-5-vinyloxazolidin-4-yl)methyl ac-
etate (4p)
4.21. (S*)-2-(tert-Butyldimethylsilyloxy)-1-[(R*)-2-
oxooxazolidin-4-yl]ethyl acetate (4k)
Colourless oil (42 mg, 46%) from carbamate 1, obtained as an
approximately 1:1 mixture of diastereoisomers. Rf 0.10 (petrol/
ethyl acetate, 2:1); nmax (thin film)/cmꢂ1 3300br m, 2959m, 1741s,
1393m, 1230m, 1044m; NMR data for trans-4p: dH (400 MHz,
CDCl3) 2.11 (3H, s, COCH3), 3.80 (1H, dtd, J 5.9, 4.4, 1.0 Hz, CHNH),
4.07 (1H, dd, J 11.5, 5.9 Hz) and 4.25 (1H, dd, J 11.5, 4.4 Hz, CH2OAc),
4.70e4.75 (1H, m, CHCH]), 5.36 (1H, app dt, J 10.5, 1.0 Hz) and 5.45
(1H, app dt, J 17.1, 1.0 Hz, ]CH2), 5.92 (1H, ddd, J 17.1, 10.5, 6.7 Hz,
CH]CH2), 6.31 (1H, br s, NH); dC (400 MHz, CDCl3) 20.6 (CH3), 56.8
(CH), 64.2 (CH2), 79.3 (CH), 119.5 (CH2), 133.6 (CH), 158.7 (C), 170.7
(C); NMR data for cis-4p: dH (400 MHz, CDCl3) 2.10 (3H, s, COCH3),
3.95 (1H, dd, J 11.4, 7.5 Hz) and 4.21 (1H, dd, J 11.4, 3.9 Hz, CH2OAc),
4.10 (1H, app td, J 7.5, 3.9 Hz, CHNH), 5.12e5.18 (1H, m, CHCH]),
5.44 (1H, app dt, J 10.4, 1.0 Hz) and 5.45 (1H, app dt, J 17.2, 1.0 Hz, ]
CH2), 5.89 (1H, ddd, J 17.2, 10.4, 6.7 Hz, CH]CH2), 6.14 (1H, br s,
NH); dC (400 MHz, CDCl3) 20.7 (CH3), 54.2 (CH), 63.2 (CH2), 78.6
(CH),121.0 (CH2),129.7 (CH),158.7 (C),170.6 (C); HRMS (ESIþ) found
208.0576, C8H11NNaO4 (MNaþ) requires 208.0580.
Pale yellow oil (104 mg, 69%) from carbamate 3k. Rf 0.59 (ethyl
acetate); nmax (thin film)/cmꢂ1 3289br, 2930m, 1751s, 1472w, 1232s,
1114m, 838m, 779w; dH (500 MHz, CDCl3) 0.08 (3H, s) and 0.08 (3H,
s, Si(CH3)2), 0.90 (9H, s, C(CH3)3), 2.13 (3H, s, COCH3), 3.74 (1H, dd, J
11.3, 5.0 Hz) and 3.82 (1H, dd, J 11.3, 3.6 Hz, CH2OSi), 4.15e4.20 (1H,
m, CHNH), 4.20e4.25 (1H, m) and 4.49 (1H, app t, J 8.7 Hz, OCH2),
4.82e4.86 (1H, m, CHOAc), 5.78 (1H, br s, NH); dC (125 MHz, CDCl3)
ꢂ5.6 (CH3), e5.4 (CH3), 18.2 (C), 20.9 (CH3), 25.8 (CH3), 53.6 (CH),
62.7 (CH2), 67.1 (CH2), 73.6 (CH), 159.3 (C), 171.4 (C); HRMS (ESIþ)
found 326.1393, C13H25NNaO5Si (MNaþ) requires 326.1394.
4.22. 2-(2-Oxooxazolidin-4-yl)propan-2-yl acetate (4l)
White solid (60 mg, 64%) from carbamate 3l. Rf 0.12 (petrol/ethyl
acetate, 2:1); mp 64e66 ꢁC; nmax (thin film)/cmꢂ1 3280br, 1737s,
1371m, 1245s, 1149m, 1022w, 994w, 770w, 721w; dH (400 MHz,
CDCl3) 1.46 and 1.48 (2ꢃ3H, s, 2ꢃ CH3), 2.01 (3H, s, COCH3), 4.05
(1H, dd, J 9.3, 4.9 Hz, CHNH), 4.26 (1H, dd, J 9.3, 4.9 Hz) and 4.42 (1H,
app t, J 9.3 Hz, OCH2), 6.97 (1H, br s, NH); dC (100 MHz, CDCl3) 20.8
(CH3), 21.2 (CH3), 22.2 (CH3), 59.6 (CH), 65.9 (CH2), 81.8 (C), 160.2
(C), 170.2 (C); HRMS (ESIþ) found 210.0733, C8H13NNaO4 (MNaþ)
requires 210.0737.
4.27. (R*)-4-[(R*)-1-Hydroxybutyl]oxazolidin-2-one (5)1e
To a solution of oxazolidinone 4g (16.0 mg, 0.080 mmol) in aq
THF (1:1, 4.0 mL) at rt was added NaOH (3.80 mg, 0.096 mmol) and
the mixture was stirred for 4 h. The reaction mixture was then
diluted with water (5.0 mL), extracted with dichloromethane
(3ꢃ10 mL) and the extracts were dried over MgSO4. Concentration
in vacuo and purification by column chromatography (ethyl ace-
tate) afforded a sample of the title compound as a pale yellow oil
(2.0 mg, 16%). Rf 0.18 (ethyl acetate); dH (400 MHz, CDCl3) 0.97 (3H,
t, J 7.1 Hz, CH3), 1.32e1.45 (3H, m, CHH0CH2CH3), 1.52e1.57 (1H, m,
CHH0CH2CH3), 2.20 (1H, d, J 6.4 Hz, OH), 3.52e3.57 (1H, m, CHOH),
4.23. (R*)-6-Methyl-2-[(R*)-2-oxooxazolidin-4-yl]hept-5-en-
2-yl acetate (4m)
Colourless oil (72 mg, 56%) from carbamate 3m. Rf 0.41 (ethyl
acetate); nmax (thin film)/ cmꢂ1 3264br, 1760s, 1371w, 1241s, 1178w,
1130w, 1021m, 943w, 769w; dH (400 MHz, CDCl3) 1.43 (3H, s, CH3),

7394
W.P. Unsworth et al. / Tetrahedron 70 (2014) 7388e7394
P.; Hadad, C. M.; Coleman, R. S.; Lowary, T. L. J. Org. Chem. 2006, 71, 8059e8070;
(k) Yoshimitsu, T.; Ino, T.; Tanaka, T. Org. Lett. 2008, 10, 5457e5460; (l) Orac, C.
M.; Zhou, S.; Means, J. A.; Boehm, D.; Bergmeier, S. C.; Hines, J. V. J. Med. Chem.
2011, 54, 6786e6795.
3.76e3.81 (1H, m, CHNH), 4.20 (1H, dd, J 8.8, 5.8 Hz) and 4.46 (1H,
app t, J 8.8 Hz, OCH2), 5.68 (1H, br s, NH); dC (100 MHz, CDCl3) 13.9
(CH3), 18.6 (CH2), 35.5 (CH2), 57.0 (CH), 67.0 (CH2), 72.8 (CH), 159.6
(C) [lit.1e 13.9, 18.7, 35.2, 57.4, 67.4, 72.7, 160.8].
10. (a) Duran, F.; Leman, L.; Ghini, A.; Burton, G.; Dauban, P.; Dodd, R. H. Org. Lett.
2002, 4, 2481e2483; (b) Guthikonda, K.; Du Bois, J. J. Am. Chem. Soc. 2002, 124,
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4.28. (4R*,5R*)-4-Hydroxymethyl-5-propyloxazolidin-2-one
€
(d) Fruit, C.; Muller, P. Tetrahedron: Asymmetry 2004, 15, 1019e1026; (e) Wehn,
(6)19
P. M.; Du Bois, J. Org. Lett. 2005, 7, 4685e4688; (f) Duran, F. J.; Ghini, A. A.;
Dauban, P.; Dodd, R. H.; Burton, G. J. Org. Chem. 2005, 70, 8613e8616; (g) Li, Z.;
Ding, X.; He, C. J. Org. Chem. 2006, 71, 5876e5880; (h) Guthikonda, K.; Wehn, P.
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A.; Duran, F.; Retailleau, P.; Dodd, R. H.; Dauban, P. Synthesis 2007, 1251e1260;
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natunga, S.; Del Valle, J. R. Tetrahedron Lett. 2009, 50, 2464e2466; (l) Wehn, P.
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5592e5599.
To a stirred solution of oxazolidinone 4g (16.0 mg, 0.080 mmol)
in aq THF (1:1, 4.0 mL) at RT was added LiOH (2.30 mg,
0.096 mmol). After 5 h, more LiOH (2.30 mg, 0.096 mmol) was
added and stirring was continued for a further 18 h. The reaction
mixture was then diluted with water (5.0 mL), extracted with
dichloromethane (3ꢃ10 mL) and the extracts were dried over
MgSO4. Concentration in vacuo afforded the title compound as
a pale yellow oil (6.0 mg, 48%). Rf 0.20 (ethyl acetate); nmax (thin
film)/ cmꢂ1 3300br, 2961m, 1733s, 1407m, 1260w, 1079m; dH
(400 MHz, CDCl3) 0.97 (3H, t, J 7.3 Hz, CH3), 1.38e1.55 (2H, m,
CH2CH3), 1.57e1.80 (2H, m, CH2CH2CH3), 3.52e3.60 (2H, m, CHNH,
CHH0OH), 3.68e3.73 (1H, m, CHH0OH), 4.35e4.40 (1H, m, OCH),
6.41 (1H, br s, NH); dC (100 MHz, CDCl3) 13.7 (CH3), 17.9 (CH2), 36.9
(CH2), 59.3 (CH), 63.6 (CH2), 78.9 (CH),160.0 (C); HRMS (ESIþ) found
182.0785, C7H13NNaO3 (MNaþ) requires 182.0788.
11. (a) Levites-Agababa, E.; Menhaji, E.; Perlson, L. N.; Rojas, C. M. Org. Lett. 2002, 4,
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We thank the EPSRC and AstraZeneca for a studentship (for
W.P.U.) and Drs. Tim Claridge and Barbara Odell, University of Ox-
ford, for supporting NMR studies.
15. Rh(II): (a) Lebel, H.; Huard, K.; Lectard, S. J. Am. Chem. Soc. 2005, 127,
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