Ring expansion of 2-(1-Hydroxyalkyl)azetidines to 4-(2-Chloroethyl) oxazolidinones

Article abstract of DOI:10.1002/ejoc.201001375

2-(1-Hydroxyalkyl)azetidines react with bis(trichloromethyl) carbonate (BTC) after basic treatment to afford 4-(2-chloroethyl)oxazolidinones. The scope of this rearrangement was examined in detail and its efficiency was shown to depend on the class of the

Full text of DOI:10.1002/ejoc.201001375

FULL PAPER
DOI: 10.1002/ejoc.201001375
Ring Expansion of 2-(1-Hydroxyalkyl)azetidines to 4-(2-Chloroethyl)-
oxazolidinones
François Couty,*[a] Bruno Drouillat,[a] and Frédéric Lemée[a]
Keywords: Ring expansion / Nitrogen heterocycles / Synthetic methods / Azetidines / Oxazolidinones
2-(1-Hydroxyalkyl)azetidines react with bis(trichloromethyl)
carbonate (BTC) after basic treatment to afford 4-(2-chloro-
ethyl)oxazolidinones. The scope of this rearrangement was
examined in detail and its efficiency was shown to depend
on the class of the reacting alcohol and on the substitution
pattern on the azetidine ring.
continuation of our interest in the chemistry of azetid-
ines,[10] we decided to evaluate the feasibility of a similar
ring expansion starting from 2-(1-hydroxyalkyl)azetidines 5
(Scheme 1). Considering the easy access to the required
starting material,[11] this ring expansion would provide an
original entry to 4-(2-chloroethyl)oxazolidinones 7, which
are susceptible to further chemical transformations.
Introduction
Oxazolidinones are among the most popular heterocycles
in organic chemistry due to the seminal work of Evans[1]
who introduced these scaffolds as chiral auxiliaries that be-
came cornerstones of asymmetric synthesis.[2] More re-
cently, the discovery of Linezolid (1, Figure 1), the first clin-
ically useful oxazolidinone antibacterial agent,[3] has
brought to light another important application of these het-
erocycles. In 2000, this antibiotic was approved by the FDA
and was shown to be active against multidrug-resistant
Gram-positive pathogens responsible for significant mor-
tality. Synthesis of oxazolidinones relies on the formation
of the cyclic carbamate by reaction of a 1,2-amino alcohol
with diverse acylating agents such as diethyl carbonate,[4]
phosgene,[5] N,NЈ-carbonyldiimidazole,[6] or carbon mon-
oxide with catalytic elemental sulfur.[7] Therefore, the ease
of preparation of oxazolidinones with functionalized side
chains depends heavily on the synthetic availability of the Scheme 1. Is the ring expansion of 2-(1-hydroxyalkyl)aziridines
corresponding amino alcohol.[8] In 2003, Ha and Lee dem-
transposable to azetidines.
onstrated that 4-(chloromethyl)oxazolidinones 4 resulted
from the reaction of the corresponding 2-hydroxyalkyl azir-
idine 2 with phosgene under basic conditions.[9] This ring
Results and Discussion
expansion involves intermediate N-acyl aziridinium 3,
which is opened regioselectively by the chloride anion. In
2-(1-Hydroxyalkyl)azetidines 8–18 chosen to conduct
this study were prepared as described previously.[11c] Exam-
ples of all classes of alcohols were used to determine the
scope of the reaction. Substitution on the azetidine ring was
also varied, and the structures of these substrates are de-
picted in Figure 2. Previously unreported azetidines (Ϯ)-11
and 14–18, as well as known (Ϯ)-8 were prepared according
to Scheme 2.
With this array of diversely substituted azetidines, the
feasibility of the rearrangement was studied. We chose the
best operating conditions described by Ha, that is, forma-
tion of the sodium alkoxide by reaction with NaH in THF,
followed by reaction with bis(trichloromethyl) carbonate
(BTC), as a safer substitute for phosgene. With these condi-
tions, we were delighted to see that (Ϯ)-8 was converted
Figure 1. Structure of Linezolid.
[a] Institut Lavoisier de Versailles, UMR 8180, Université de
Versailles St-Quentin en Yvelines,
45, av. des Etats-Unis, 78035 Versailles Cedex, France
Fax: +33-1-39254452
E-mail: couty@chimie.uvsq.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001375.
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Eur. J. Org. Chem. 2011, 794–801

Ring Expansion of 2-(1-Hydroxyalkyl)azetidines
Figure 2. Structure of 2-(1-hydroxyalkyl)azetidines used in this
study.
into 4-(2-chloroethyl)oxazolidinone 33 in quantitative yield
after 1 h at room temperature. Encouraged by this result,
the scope of this reaction was examined with other sub-
strates, and the results are presented in Table 1.
The yield of this reaction appears to depend on the sub-
stitution pattern of the starting azetidine. In most cases
(Table 1, Entries 2, 4, 5, and 7–10), the reaction was clean.
In some cases, the low yields are due to incomplete conver-
sion, as the starting material was easily detected or isolated
after workup (20–30% average yield). In other cases, the
low yields are explained by side reactions; this is the case
for Entry 6, where only 2-(chloromethyl)azetidine 38[11c]
was isolated among unidentified byproducts. Formation of
Scheme 2. Synthesis of previously unreported 2-(1-hydroxyalkyl)-
azetidines.
this compound can be explained by attack of the chloride and results in starting material. Possible competitive reac-
anion at the oxomethylene position instead of at the C-4 tion of the amine in the case of primary alcohols is proven
position of the azetidinium, which is hindered by the methyl experimentally by the nature of side product 44, whose for-
substituent (Scheme 3). This is also the case for (Ϯ)-11 mation can only be explained by competitive attack on BTC
(Table 1, Entry 4). In this experiment, compound 44 was by the nitrogen. Simple steric factors hampering the attack
isolated in 19% yield. Its formation was rationalized by the of the chloride anion on intermediate 6 cannot be ruled
carbocationic nature of the intermediate bicyclic azetidin- out.[14]
ium, which undergoes a 1,2-hydride shift to furnish alde-
Starting with secondary alcohol (Ϯ)-17, attempts to opti-
hyde 44 (Scheme 3). Tertiary alcohol 18 (Table 1, Entry 11) mize the yield by varying the reaction conditions did not
was also reluctant to undergo rearrangement, and most of meet with much success. More polar solvents, such as
the starting material was recovered. This lack of reactivity DME, the presence of additives, such as crown ethers, the
contrasts the work of Ha[9] in the lower homologue series. nature of the base (BuLi or KHMDS), and the addition of
One possible explanation is the enhanced nucleophilicity of phosgene instead of BTC were screened extensively but gave
the nitrogen in the azetidine ring, compared to the aziridine. no significant improvement in the yield of (Ϯ)-42.
Thus, if the alkoxide is too encumbered (which is especially
Finally, post functionalization of 4-(2-chloroethyl)ox-
true with tertiary alcohols), the nitrogen atom of the azetid- azolidinone 33 was briefly examined. Substitution of the
ine competes to react with BTC and gives a double salt, chloride by azide or cyanide occurred readily to give 45 and
which precipitates in the reaction medium and does not 46, respectively. More interestingly, treatment of 33 with a
evolve further. Upon basic workup, this salt decomposes slight excess amount of BuLi in THF promoted benzylic
Eur. J. Org. Chem. 2011, 794–801
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795

F. Couty, B. Drouillat, F. Lemée
FULL PAPER
Table 1. Scope of the rearrangement.
Scheme 3. Mechanism of formation of side products 38 and 44.
lithiation followed by kinetically controlled intramolecular
alkylation to afford 47 in a diastereoselective manner to-
gether with starting material 33 (3:1 ratio by NMR spec-
troscopy). Protracted reaction time or excess amounts of
BuLi did not totally consume the starting material, but in-
duced formation of diastereoisomer 48,[15] which probably
arises from further lithiation of 47, followed by equilibra-
tion (Scheme 4).
Scheme 4. Post functionalization of oxazolidinone 33.
Conclusions
In conclusion, we have demonstrated that 2-(1-hy-
droxymethyl)azetidines can be converted into 4-(2-chloro-
ethyl)oxazolidinones by reaction with BTC. The scope of
the reaction was examined and was shown to be restricted
to primary and secondary alcohols on the azetidinic side
chain. Furthermore, azetidines substituted at C-4 or disub-
stituted at C-2 failed to react or gave side products that
allowed insight into the mechanism. Yields are modest,
which is attributed to the competitive reaction of the azetid-
inic nitrogen with BTC that leads to unreactive intermedi-
ates. Starting material can be recovered in these cases by
simple acidic/basic treatment. Work is in progress to further
examine the reactivity of functionalized azetidines with
phosgene.
[a] Yield of isolated product. [b] Yield was improved to 48% (86%
based on recovered starting material) when KHMDS was used as
base instead of NaH.
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Eur. J. Org. Chem. 2011, 794–801

Ring Expansion of 2-(1-Hydroxyalkyl)azetidines
(CH2), 81.1 (Cq), 126.9, 127.2, 127.5 (CHAr), 139.4 (CqAr), 173.1
Experimental Section
(CO) ppm. IR (NaCl, film) ν
= 3490, 2976, 1721, 1141, 729,
˜
max
General Comments: 1H and 13C NMR spectra were recorded with a
Bruker Avance spectrometer at 200 or 300 MHz and 75 or 50 MHz,
respectively; chemical shifts are reported in ppm from TMS. Op-
tical rotations were determined with a Perkin–Elmer 141 instru-
ment. All reactions were carried out under an atmosphere of argon.
Column chromatography was performed on a silica gel 230–
400 mesh by using various mixtures of diethyl ether (Et2O), ethyl
acetate (AcOEt), petroleum ether (PE), and cyclohexane (CyH).
TLCs were run on Merck Kieselgel 60F254 plates. THF and toluene
were dried by a dehydrating system MB-SPS 800 (Mbraun).
Dichloromethane (DCM) was distilled from calcium hydride. The
mention of a “usual workup“ means: (i) decantation of the organic
layer, (ii) extraction of the aqueous layer with specified solvent,
(iii) drying of the combined organic layers with MgSO4, (iv) solvent
evaporation under reduced pressure. Isomeric ratios were deter-
mined by NMR spectroscopic analysis of crude reaction mixtures
before purification. High-resolution mass spectra (HRMS) were
obtained with a Water Micromass Q-Tof Micro instrument.
697 cm–1. HRMS: calcd. for C16H26NO3 [M + H]+ 280.1913; found
280.1898.
β-Amino Chloride 23: Following the procedure described above for
22, compound 23 was obtained as an oil (8.2 g, 96%) and was
1
used as such for the next step. Rf = 0.8 (PE/AcOEt, 8:2). H NMR
(200 MHz, CDCl3): δ = 1.28 (d, J = 7.2 Hz, 3 H, Me), 1.48 (s, 9
H, tBu), 2.88–3.152 (m, 2 H, NCH2), 3.33–3.42 (m, 3 H, CHMe
and CH2Cl), 3.77 (d, part of AB syst., J = 14.3 Hz, 1 H,
NCHHPh), 3.90 (d, part of a AB syst., J = 14.3 Hz, 1 H,
NCHHPh), 7.24–7.37 (m, 5 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3): δ = 16.1, 28.3 (CH3), 43.0, 53.1, 56.5 (CH2), 59.2 (CH),
81.0 (Cq), 127.1, 128.3, 128.5 (CHAr), 139.9 (CqAr), 173.1 (CO)
ppm. IR (NaCl, film) νmax = 2977, 1722, 1367, 1141, 728, 697 cm–1.
˜
HRMS: calcd. for C16H25ClNO2 [M + H]+ 298.1496; found
298.1479.
tert-Butyl Ester 25: Following the procedure described above for
the preparation of 24, compound 25 was obtained as an oil (6.6 g,
83%) after purification by flash chromatography (PE/AcOEt, 9:1;
Rf = 0.7). 1H NMR (200 MHz, CDCl3): δ = 1.45 (s, 3 H, Me), 1.49
(s, 9 H, tBu), 1.81–1.93 (m, 1 H, 3-H), 2.48–2.60 (m, 1 H, 3Ј-H),
2.99–3.10 (m, 1 H, 4-H), 3.16–3.26 (m, 1 H, 4Ј-H), 3.55 (d, part of
AB syst., J = 12.7 Hz, 1 H, NCHHPh), 3.80 (d, part of a AB syst.,
J = 12.7 Hz, 1 H, NCHHPh), 7.28–7.32 (m, 5 H, Ar) ppm. 13C
NMR (75 MHz, CDCl3): δ = 18.9, 28.2 (CH3), 28.4, 49.0, 55.7
(CH2), 68.3 (CH), 80.6 (Cq), 126.9, 128.3, 128.8 (CHAr), 138.5
tert-Butyl Ester 24: To a solution of N-benzylethanolamine 19 (5 g,
33.1 mmol) in acetonitrile (150 mL) was added sodium iodide (1 g,
6.7 mmol), K2CO3 (4.7 g, 34 mmol), and tert-butyl chloroacetate
(5 mL, 35 mmol). The reaction mixture was heated at reflux over-
night, cooled to room temperature, and concentrated under re-
duced pressure. The residue was partitioned between water and
ether, washed with 5wt.-% aqueous Na2S2O3, and treated following
usual workup to afford a quantitative yield of 20. This residue was
dissolved in DCM (200 mL) and thionyl chloride (4.7 mL,
63.9 mmol) was added dropwise. After heating the mixture at reflux
for 1 h, it was cooled to room temperature and neutralized by care-
ful addition of a saturated aqueous solution of NaHCO3 (caution:
gas evolution!). Usual workup (DCM) gave quantitative yield of
22. Crude 22 was dissolved in dry THF (300 mL) and tBuOK
(4.48 g, 40 mmol) was added portionwise at 0 °C. The reaction mix-
ture was stirred at room temperature for 15 min and hydrolyzed by
the addition of a saturated aqueous solution of NH4Cl (15 mL).
Partial concentration under reduced pressure was followed by usual
workup (AcOEt) to give crude 24, which was purified by flash
chromatography (PE/AcOEt, 85:15; Rf = 0.4). Compound 24 was
obtained as an oil (6.45 g, 79% overall) that showed spectroscopic
data in accordance with literature data.[16]
(CqAr), 174.0 (CO) ppm. IR (NaCl, film) νmax = 2920, 2851, 1710,
˜
1260, 759, 701 cm–1. HRMS: calcd. for C16H24NO2 [M + H]+
262.1729; found 262.1780.
β-Amino Alcohol (؎)-11: Following the procedure described above
for the reduction of 24, compound 11 was obtained as an oil (3.6 g,
82%) and was used as such for the next step. Rf = 0.2 (DCM/
1
MeOH/16 m aq. NH3, 94.5:5:0.5). H NMR (200 MHz, CDCl3): δ
= 1.26 (s, 3 H, Me), 1.51–1.62 (m, 1 H, 3-H), 2.32–2.46 (m, 1 H,
3Ј-H), 2.99–3.14 (m, 3 H, 4-H and 5-H), 3.20–3.29 (m, 1 H, 4Ј-H),
3.47 (d, part of AB syst., J = 13.1 Hz, 1 H, NCHHPh), 3.65 (d,
part of a AB syst., J = 13.1 Hz, 1 H, NCHHPh), 7.26–7.31 (m, 5
H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.2 (CH3), 25.3,
48.8, 54.3, 66.0 (CH2), 66.9 (Cq), 127.1, 128.2, 128.4 (CHAr), 138.5
(CqAr) ppm. HRMS: calcd. for C12H18NO [M + H]+ 192.1388;
found 192.1380.
2-(1-Hydroxyalkyl)azetidine (؎)-8: To a solution of ester 24 (6 g,
24.5 mmol) in THF (100 mL) was added portionwise LiAlH4
(1.9 g, 49 mmol). The reaction mixture was stirred for 2 h at 0 °C
and hydrolyzed by successive dropwise addition of water (1.9 mL),
2 m NaOH (1.9 mL), and water (3.8 mL). After stirring at room
temperature for 2 h, THF (50 mL) was added, and the reaction
mixture was filtered. The solid was washed with THF (3ϫ50 mL),
and the filtrate was concentrated under reduced pressure to give 8
as a clear oil that crystallized on standing (m.p. 68 °C, 4.25 g,
98%). This compound was used for the next steps and showed spec-
troscopic data in accordance with literature data.[17]
Ketone 27: MeLi (1.6 m in diethyl ether, 3.36 mL, 5.37 mmol) was
added dropwise to a solution of 26[13] (500 mg, 2.69 mmol) in tolu-
ene (15 mL) at 0 °C. The reaction mixture was stirred at 0 °C for
1 h and hydrolyzed by the addition of a saturated aqueous solution
of NH4Cl (15 mL). Usual workup gave a crude oil, which was a
mixture of 27 and the corresponding imine. The residue was puri-
fied by flash chromatography (PE/AcOEt, 9:1; Rf = 0.3) to give
compound 27 as an oil (300 mg, 55%). [α]2D0 = +1.3 (c = 0.8,
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 1.17 (d, J = 9 Hz, 3 H,
Me), 2.06–2.26 (m, 2 H, 3-H), 2.39 (s, 3 H, CH3CO), 2.78–2.86 (m,
1 H, 4-H), 3.15 (dt, J = 2.7, 7.3 Hz, 1 H, 4Ј-H), 3.44 (q, J = 6.5 Hz,
1 H, CHPh), 3.74 (t, J = 8.7 Hz, 1 H, 2-H), 7.26–7.33 (m, 5 H, Ar)
ppm. 13C NMR (75 MHz, CDCl3): δ = 20.8 (CH2), 21.3, 25.3
(CH3), 49.9 (CH2), 67.6, 71.5 (CH), 127.2, 128.4 (CHAr), 142.9
β-Amino Alcohol 21: Following the procedure described above for
20 by using tert-butyl 2-bromopropionate[18] as alkylating agent,
compound 21 was obtained as an oil (8.3 g, 90%) after purification
by flash chromatography (PE/AcOEt, 8:2; Rf = 0.6). 1H NMR
(200 MHz, CDCl3): δ = 1.24 (d, J = 7.1 Hz, 3 H, Me), 1.48 (s, 9
H, tBu), 2.72–2.92 (m, 2 H, NCH2), 3.41 (q, J = 7.1 Hz, 1 H,
CHMe), 3.45–3.54 (m, 2 H, CH2OH), 3.73 (d, part of AB syst., J
(CqAr), 211.1 (CO) ppm. IR (NaCl, film) νmax = 2965, 2840, 1703,
˜
1451, 1348, 697 cm–1. HRMS: calcd. for C13H18NO [M + H]+
204.1388; found 204.1368.
= 14 Hz, 1 H, NCHHPh), 3.80 (d, part of a AB syst., J = 14 Hz, Ketone 28: BuLi (1.6 m in hexane, 2.85 mL, 4.57 mmol) was added
1 H, NCHHPh), 7.27–7.34 (m, 5 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3): δ = 14.2, 28.2 (CH3), 52.0, 55.3 (CH2), 58.0, (CH), 58.8
dropwise to a solution of 26[13] (425 mg, 2.28 mmol) in THF
(20 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h
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F. Couty, B. Drouillat, F. Lemée
FULL PAPER
and hydrolyzed by the addition of a saturated aqueous solution of
NH4Cl (15 mL). Usual workup gave a crude oil, which was a mix-
ture of 28 and the corresponding imine. This residue was dissolved
in AcOEt (50 mL) and silica gel (10 g) was added. This suspension
was stirred overnight at room temperature, filtered, and concen-
trated under reduced pressure. Purification by flash chromatog-
raphy (PE/Et2O, 1:1; Rf = 0.5) gave compound 28 as an oil (477 mg,
85%). [α]2D0 = +152 (c = 1.0, CHCl3). 1H NMR (200 MHz, CDCl3):
δ = 0.94 (t, J = 7.2 Hz, 3 H, Me), 1.06 (d, J = 6.5 Hz, 3 H, Me),
1.22–1.44 (m, 2 H, CH2), 1.52–1.67 (m, 2 H, CH2), 2.00–2.20 (m,
2 H, CH2CO), 2.57–2.83 (m, 3 H, 4-H and 3-H), 3.12 (dt, J = 2.8,
7.6 Hz, 1 H, 4Ј-H), 3.38 (q, J = 6.5 Hz, 1 H, CHPh), 3.72 (t, J =
8.7 Hz, 1 H, 2-H), 7.26–7.34 (m, 5 H, Ar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.0 (CH3), 20.9 (CH2), 21.3 (CH3), 22.5,
25.5, 49.8 (CH2), 67.6, 71.4 (CH) 127.1, 127.3, 128.3 (CHAr), 142.9
(75 MHz, CDCl3): δ = 14.1 (CH3) 14.8 (CH2), 22.3 (CH3), 23.0,
28.2, 31.4 49.6 (CH2), 67.1, 68.3, 70.31 (CH), 127.1, 128.4 (CHAr),
143.6 (CqAr) ppm. IR (NaCl, film) ν
= 3416, 2834, 1047, 726,
˜
max
696 cm–1. HRMS: calcd. for C16H26NO [M + H]+ 248.2014; found
248.2013.
2-(1-Hydroxyalkyl)azetidine 16: Following the above procedure de-
scribed for 14, compound 16 was obtained as a solid (305 mg,
57%); after purification by flash chromatography (PE/AcOEt,
75:25; Rf = 0.4). M.p. 93 °C. [α]2D0 = +121 (c = 0.9, CHCl3). 1H
NMR (200 MHz, CDCl3): δ = 1.40 (d, J = 6.4 Hz, 1 H, Me), 2.68
(q, J = 8.2 Hz, 1 H, 4-H), 2.98–3.05 (m, 1 H, 4Ј-H), 3.56–3.70 (m,
2 H, 2-H and CHMe), 4.84 (d, J = 3.0 Hz, 1 H, CHOH), 7.27–
7.39 (m, 10 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.8
(CH2), 22.1 (CH3), 48.9, 66.9, 69.1, 72.1 (CH), 125.6, 127.0, 128.1,
128.4 (CHAr), 140.0, 143.4 (CqAr) ppm. IR (NaCl, Nujol) ν
=
˜
max
(CqAr), 212.3 (CO) ppm. IR (NaCl, film) νmax = 2956, 1631, 1453,
˜
3500, 2862, 1450, 762, 698 cm–1. HRMS: calcd. for C18H22NO [M
+ H]+ 268.1718; found 268.1701.
1180, 729, 697 cm–1. HRMS: calcd. for C16H24NO [M + H]+
246.1858; found 246.1847.
Ketone 31: Following the procedure for the preparation of 28, com-
pound 31 was obtained as an oil (1.18 g, 88%) after purification
by flash chromatography (PE/AcOEt, 1:1; Rf = 0.2). 1H NMR
(200 MHz, CDCl3): δ = 0.86 (t, J = 6.5 Hz, 3 H, Me), 1.13–1.31
(m, 2 H, CH2), 1.36–1.51 (m, 2 H, CH2), 2.10–2.30 (m, 3 H,
CHHCO and 3-H), 2.46–2.62 (m, 1 H, CHHCO), 2.87–2.99 (m, 1
H, 4-H), 3.27–3.35 (m, 1 H, 4Ј-H), 3.57 (d, part of AB syst., J =
12.5 Hz, 1 H, NCHHPh), 3.67 (t, J = 8.7 Hz, 1 H, 2-H), 3.73 (d,
part of AB syst., J = 12.5 Hz, 1 H, NCHHPh), 7.26–7.31 (m, 5 H,
Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.9 (CH3), 21.8, 22.3,
25.1, 32.1, 50.9, 63.0 (CH2), 71.4 (CH), 127.3, 128.4, 129.0 (CHAr),
137.4 (CqAr), 212.0 (CO) ppm. HRMS: calcd. for C16H24NO [M
+ H]+ 246.1658; found 246.1847.
Ketone 29: Following the above procedure with PhMgBr and run-
ning the reaction in toluene instead of THF, compound 29 was
obtained as a yellow solid (350 mg, 77%) after purification by flash
chromatography (PE/AcOEt, 7:3; Rf = 0.5). M.p. 62 °C. [α]2D0
=
1
+1.6 (c = 0.5, CHCl3). H NMR (200 MHz, CDCl3): δ = 1.19 (d,
J = 6.5 Hz, 3 H, Me), 2.17–2.46 (m, 2 H, 3-H), 2.85–2.97 (m, 1 H,
2-H), 3.15–3.24 (m, 1 H, 2Ј-H), 3.49 (q, J = 6.5 Hz, 1 H, CHPh),
4.53 (t, J = 8.8 Hz, 1 H, 2-H), 7.26–7.63 (m, 10 H, Ar) ppm. 13C
NMR (75 MHz, CDCl3): δ = 22.0 (CH3), 23.9, 50.3 (CH2), 68.4,
69.4 (CH), 126.8, 127.2, 127.6, 128.4, 128.6, 133.2 (CHAr), 135.7,
143.4 (CqAr), 199.3 (CO) ppm. IR (NaCl, film) νmax = 2964, 2851,
˜
1687, 1596, 1447, 1369, 1219, 876, 699 cm–1. HRMS: calcd. for
C18H20NO [M + H]+ 266.1545; found 266.1536.
2-(1-Hydroxyalkyl)azetidine (؎)-17: Following the procedure de-
scribed above for the reduction of 24, compound 17 was obtained
as an oil (633 mg, 88%) and was used as such for the next step. Rf
2-(1-Hydroxyalkyl)azetidine 14: To a solution of ketone 28 (336 mg,
1.66 mmol) in MeOH (10 mL) was added ZnBr2 (412 mg,
1.83 mmol). The reaction mixture was stirred at room temperature
for 30 min followed by the portionwise addition of NaBH4 (95 mg,
2.49 mmol). After stirring for an additional 30 min., ethylene di-
amine (0.5 mL, 7.47 mmol) was added, and the mixture was stirred
for 1.5 h. AcOEt (25 mL) and water (25 mL) were added, and the
organic layer was separated. The aqueous layer was extracted with
AcOEt (25 mL), washed with 1 n NaOH (25 mL) and 20% aq.
NH3 (25 mL), dried with MgSO4, and concentrated under reduced
pressure. The residue was purified by flash chromatography (PE/
AcOEt, 1:1; Rf = 0.3), to give compound 14 as an oil (202 mg,
1
= 0.2 (PE/AcOEt, 1:1). H NMR (200 MHz, CDCl3): δ = 0.88 (t,
J = 6.5 Hz, 3 H, Me), 1.18–1.35 (m, 6 H, CH2), 1.71–1.85 (m, 1 H,
3-H), 2.07–2.95 (m, 1 H, 3Ј-H), 2.83–2.95 (m, 1 H, 4-H), 3.22–3.35
(m, 3 H, 2-H, 4Ј-H and CHOH), 3.53 (d, part of AB syst., J =
12.7 Hz, 1 H, NCHHPh), 3.70 (d, part of a AB syst., J = 12.7 Hz,
1 H, NCHHPh), 7.27–7.30 (m, 5 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3): δ = 14.0 (CH3), 16.0, 22.8, 27.9, 31.0, 51.0, 61.5 (CH2),
68.4, 69.5 (CH) 127.1, 128.3, 128.6 (CHAr), 138.1 (CqAr) ppm. IR
(NaCl, film) νmax = 2927, 1453, 1167, 1028, 733, 698 cm–1. HRMS:
˜
calcd. for C15H24NO [M + H]+ 234.1858; found 234.1855.
1
59%). [α]2D0 = +97 (c = 1.1, CHCl3). H NMR (200 MHz, CDCl3):
2-(1-Hydroxyalkyl)azetidine 18: MeLi (1.6 m in diethyl ether, 6 mL,
9.51 mmol) was added dropwise to a solution of 32 (740 mg,
3.17 mmol) in THF (13 mL) at 0 °C. The reaction mixture was
stirred at 0 °C for 1 h and hydrolyzed by the addition of a saturated
aqueous solution of NH4Cl (45 mL). Usual workup gave a residue,
which was purified by flash chromatography (PE/AcOEt, 5:5; Rf =
0.1) to give compound 18 as an oil (396 mg, 57%). [α]2D0 = +1.5 (c
= 1.36, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.67 (s, 3 H,
Me), 1.01 (s, 3 H, Me), 1.32 (d, J = 6.5 Hz, 3 H, Me), 1.84–2.02
(m, 2 H, 3-H), 2.29 (br. s, 1 H, OH), 3.01–3.09 (m, 1 H, 4-H), 3.23
(m, 2 H, 2-H and 4Ј-H), 3.57 (q, J = 6.5 Hz, 1 H, CHPh), 7.22–
7.35 (m, 5 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.9
(CH3), 18.1 (CH2), 24.0, 26.7 (CH3), 46.8 (CH2), 65.1 (CH), 69.9
(CqOH), 73.2 (CH2), 127.4, 127.7, 128.5 (CHAr), 144.4 (CqAr)
δ = 1.01 (d, J = 6.3 Hz, 3 H, Me), 1.22 (d, J = 6.6 Hz, 1 H, Me),
1.65–1.79 (m, 1 H, 3-H), 1.98–2.17 (m, 1 H, 3-H), 2.61–2.74 (m, 1
H, 2-H), 2.92–3.01 (m, 1 H, 2Ј-H), 3.32 (dt, J = 6.5, 8.0 Hz, 1 H,
2-H), 3.48 (q, J = 6.6 Hz, 1 H, CHPh), 3.76–3.85 (m, 1 H, CHOH),
7.26–7.30 (m, 5 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ =
14.5, 16.6, 22.3 (CH3), 49.3 (CH2), 66.1, 67.1, 69.1 (CH), 127.1,
128.4 (CHAr), 143.7 (CqAr) ppm. IR (NaCl, film) ν
= 3495,
˜
max
2844, 1452, 1025, 757, 699 cm–1. HRMS: calcd. for C13H20NO [M
+ H]+ 206.1545; found 206.1517.
2-(1-Hydroxyalkyl)azetidine 15: Following the above procedure de-
scribed for 14, compound 15 was obtained as an oil (306 mg, 68%)
after purification by flash chromatography (PE/AcOEt, 1:1; Rf =
0.6). [α]2D0 = +88 (c = 0.9, CHCl3). 1H NMR (200 MHz, CDCl3): δ
= 0.90 (t, J = 6.9 Hz, 3 H, Me), 1.22 (d, J = 6.9 Hz, 1 H, Me),
1.27–1.55 (m, 6 H, CH2), 1.64–1.79 (m, 1 H, 3-H), 1.98–2.17 (m, 1
H, 3-H), 2.59–2.74 (m, 1 H, 4-H), 2.92–2.99 (m, 1 H, 4Ј-H), 3.39
(dt, J = 3.3, 8.3 Hz, 1 H, 2-H), 3.48 (q, J = 6.5 Hz, 1 H, CHPh),
ppm. IR (NaCl, film) ν
= 3572, 3428, 2969, 1452, 1370, 1164,
˜
max
946, 749, 699 cm–1. HRMS: calcd. for C14H21NO [M + H]+
220.1701; found 220.1698.
General Procedure for the Reaction of 2-(1-Hydroxyalkyl)azetidines
3.60–3.68 (m, 1 H, CHOH), 7.24–7.28 (m, 5 H, Ar) ppm. 13C NMR with BTC: Sodium hydride (60 wt.-% in mineral oil, 470 mg,
798
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 794–801

Ring Expansion of 2-(1-Hydroxyalkyl)azetidines
11.85 mmol) was added portionwise to a solution of azetidine
(3.95 mmol) in dry THF (30 mL) at 0 °C. After the suspension was
stirred at 0 °C for 10 min, bis(trichloromethyl) carbonate (470 mg,
1.58 mmol) was added, and the mixture was stirred at room tem-
perature for 1 h. After that time, the reaction mixture was treated
with a saturated aqueous solution of NH4Cl (20 mL) and water
4.65 (s, 2 H, NCH2Ph, one rotamer), 7.22–7.31 (m, 5 H, Ar), 9.50
(d, J = 1.1 Hz, 1 H, CHO) ppm. 13C NMR (50 MHz, CDCl3): δ =
13.4 (Me), 27.4 and 28.3 (CH2, two rotamers), 43.7 and 43.8 (CH
two rotamers), 47.0 and 48.0 (CH2 two rotamers), 52.5 and 54.4
(CH2, two rotamers), 127.2, 128.2, 128.9, (CHAr), 135.3 and 135.6
(CqAr two rotamers), 203.2 and 203.5 (CO) ppm. HRMS: calcd.
(20 mL). Usual workup (AcOEt) gave a residue that was purified for C13H16ClNO2Na [M + Na]+ 276.0767; found 276.0763.
by flash chromatography. Unreacted starting material was reco-
Oxazolidinone: 37: Yield 529 mg, 37%. Purified by flash
vered by alkaline treatment of the aqueous layer (1 n NaOH), fol-
chromatography (PE/AcOEt, 75:25; Rf = 0.6). Oil. 1H NMR
lowed by extraction with AcOEt.
(300 MHz, CDCl3): δ = 2.25–2.35 (m, 1 H, CHCH2Cl), 3.43–3.72
(m, 4 H, CH2O and CH2Cl), 3.82–3.91 (m, 1 H, 4-H), 4.11 (d, part
of AB syst., J = 15.2 Hz, 1 H, NCHHPh), 4.15–4.22 (m, 2 H,
CH2O), 4.44 (s, 2 H, CH2OBn), 4.81 (d, part of AB syst., J =
15.2 Hz, 1 H, NCHHPh), 7.21–7.37 (m, 10 H, Ar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 39.7 (CH2CH2Cl), 41.7 (CH), 46.6 (CH2),
56.3 (CH), 64.3, 67.6, 73.6 (CH2), 127.2, 127.6, 127.8, 127.9, 128.2,
129.0 (CHAr), 135.4, 137.4 (CqAr), 158.6 (CO) ppm. IR (NaCl,
Oxazolidinone 33: Yield: 2.33 g, quant. No purification by flash
chromatography needed. Oil. Rf = 0.8 (PE/AcOEt, 7:3). H NMR
1
(300 MHz, CDCl3): δ = 1.89–1.96 (m, 1 H, CHHCH2Cl), 2.13–2.26
(m, 1 H, CHHCH2Cl), 3.47 (t, J = 6.4 Hz, 2 H, CH2Cl), 3.68–3.81
(m, 1 H, 4-H), 4.05 (dd, J = 8.4, 6.4 Hz, 1 H, 5-H), 4.13 (d, part
of AB syst., J = 15.3 Hz, 1 H, NCHHPh), 4.41 (t, J = 8.6 Hz, 1
H, 5Ј-H), 4.74 (d, part of AB syst., J = 15.3 Hz, 1 H, NCHHPh),
7.31–7.43 (m, 5 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ =
34.5, 39.9, 46.4 (CH2) 53.0 (CH), 67.3 (CH2), 128.1, 128.2, 128.9
film) ν
= 2929, 1747, 1450, 749, 698, 685 cm–1. HRMS: calcd.
˜
max
for C30H22ClNO3Na [M + Na]+ 382.1186; found 382.1183.
(CHAr), 135.7 (CqAr), 158.3 (CO) ppm. IR (NaCl, film) ν
=
˜
max
Chloroazetidine 38: Yield: 85 mg, 15%. Purified by flash
chromatography (PE/AcOEt, 95:5; Rf = 0.17). [α]2D0 = –5.1 (c = 0.3,
CHCl3). H NMR (300 MHz, CDCl3): δ = 1.03 (d, J = 6.0 Hz, 3
3490, 2928, 1452, 758, 699 cm–1. HRMS: calcd. for
C12H14ClNO2Na [M + Na]+ 262.0614; found 262.0611.
1
H, Me), 2.81–2.87 (m, 1 H, 3-H), 3.07–3.16 (m, 1 H, 4-H), 3.31–
3.39 (m, 3 H, 2-H, CH2Cl), 3.71 (d, part of AB syst., J = 12.7 Hz,
1 H, NCHHPh), 3.78 (d, part of AB syst., J = 12.7 Hz, 1 H,
NCHHPh), 7.11–7.32 (m, 10 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3): δ = 21.0 (Me), 47.7 (CH2Cl), 49.9 (CH), 61.4 (NCH2),
65.8, 69.4 (CH), 126.7, 127.2, 127.5, 128.3, 128.4, 129.4 (CHAr),
Oxazolidinone 34: Yield: 529 mg, 53%. Purified by flash
chromatography (PE/AcOEt, 1:1; Rf = 0.75). M.p. 63 °C. [α]2D0
=
1
–69 (c = 0.7, DCM). H NMR (300 MHz, CDCl3): δ = 1.62 (d, J
= 7.1 Hz, 3 H, Me), 1.85–1.97 (m, 1 H, CHHCH2Cl), 2.06–2.18
(m, 1 H, CHHCH2Cl), 3.25–3.41 (m, 2 H, CH2Cl), 3.92 (dd, J =
5.8, 8.2 Hz, 1 H, CHHO), 4.18 (t, J = 8.9 Hz, 1 H, CHHO), 5.06
(q, J = 8.9 Hz, 1 H, NCHMePh), 7.20–7.34 (m, 5 H, Ar) ppm. 13
C
138.0, 140.2 (CqAr) ppm. IR (NaCl, film) νmax = 3028, 2918, 1602,
˜
1452, 1366, 1109, 739, 695 cm–1. HRMS: calcd. for C18H21ClN [M
+ H]+ 286.1363; found 286.1367.
NMR (75 MHz, CDCl3): δ = 18.8 (Me), 36.7 (CH2CH2Cl), 39.9
(CH2Cl), 52.9, 53.1 (CH), 67.1 (CH2O), 127.3, 128.1, 128.9
(CHAr), 139.0 (CqAr), 158.0 (CO) ppm. HRMS: calcd. for
C13H17ClNO2 [M + H]+ 254.0948; found 254.0951.
Oxazolidinone 39: Yield: 382 mg, 41%. Purified by flash
chromatography (PE/AcOEt, 75:25; Rf = 0.45). M.p. 61 °C. [α]2D0
=
1
+2.6 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ = 1.33 (d,
J = 7.2 Hz, 3 H, Me), 1.70 (d, J = 7.2 Hz, 3 H, Me), 1.95–2.18 (m,
2 H, CH2CH2Cl), 3.30–3.46 (m, 2 H, CH2Cl), 3.60 (dt, J = 3.2,
8.0 Hz, 1 H, 4-H), 4.48–4.57 (m, 1 H, 5-H), 5.13 (q, J = 7.2 Hz, 1
H, NCHMePh), 7.29–7.42 (m, 5 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3): δ = 14.8, 18.7 (Me), 32.1 (CH2CH2Cl), 40.6 (CH2Cl), 53.1,
55.7 (CH), 74.0 (CH2O), 127.2, 128.0, 128.9 (CHAr), 139.6 (CqAr),
157.8 (CO) ppm. HRMS: calcd. for C14H18ClNO2Na [M + Na]+
290.0924; found 290.0923.
Oxazolidinone 35: Yield 830 mg, 83%. Purified by flash chromatog-
raphy (PE/AcOEt, 1:1; Rf = 0.80). Oil. [α]2D0 = +4 (c = 1.1, DCM).
1H NMR (300 MHz, CDCl3): δ = 1.42–1.53 (m, 1 H, CHHCH2Cl),
1.59–1.70 (m, 1 H, CHHCH2Cl), 1.63 (d, J = 7.1 Hz, 3 H, Me),
3.20–3.25 (m, 2 H, CH2Cl), 3.93 (dd, J = 8.1, 8.3 Hz, 1 H, CHHO),
3.95–4.05 (m, 1 H, 3-H), 4.35 (t, J = 8.1 Hz, 1 H, CHHO), 5.06 (q,
J = 7.1 Hz, 1 H, NCHMePh), 7.19–7.37 (m, 5 H, Ar) ppm. 13C
NMR (75 MHz, CDCl3): δ = 16.4 (Me), 35.5 (CH2CH2Cl), 40.1
(CH2Cl), 51.7, 52.1 (CH), 67.3 (CH2O), 127.0, 127.9, 128.7
(CHAr), 141.0 (CqAr), 158.2 (CO) ppm. HRMS: calcd. for
C13H16ClNO2Na [M + Na]+ 276.0767; found 276.0766.
Oxazolidinone 40: Yield: 357 mg, 33%. Purified by flash
chromatography (PE/AcOEt, 75:25; Rf = 0.64). Oil. [α]2D0 = –13.3
(c = 0.8, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.89 (t, J =
6.6 Hz, 3 H, Me), 1.15–1.60 (m, 6 H, CH2), 1.69 (d, J = 7.2 Hz, 3
H, Me), 1.93–2.17 (m, 2 H, CH2CH2Cl), 3.40 (br. t, J = 7.5 Hz, 2
H, CH2Cl), 3.56 (dt, J = 3.4, 7.2 Hz, 1 H, 4-H), 4.25–4.35 (m, 1
H, 5-H), 5.11 (q, J = 7.2 Hz, 1 H, NCHMePh), 7.30–7.38 (m, 5 H,
Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.8, 18.6 (Me), 22.3,
28.0, 28.8, 32.5, 40.4 (CH2), 53.2, 55.5, 78.3 (CH), 127.1, 127.9,
128.8 (CHAr), 139.6 (CqAr), 157.7 (CO) ppm. IR (NaCl, film)
Oxazolidinone 36: Yield 349 mg, 35%. Purified by flash chromatog-
raphy (PE/AcOEt, 75:25; Rf = 0.5). Oil. 1H NMR (300 MHz,
CDCl3): δ = 1.18 (s, 3 H, Me), 1.08–2.03 (m, 2 H, CH2CH2Cl),
3.13–3.22 (m, 1 H, CH2CHHCl), 3.32–3.41 (m, 1 H, CH2CHHCl),
3.92 (d, part of AB syst., J = 8.9 Hz, 1 H, NCHHPh), 4.19 (d, part
of AB syst., J = 8.9 Hz, 1 H, NCHHPh), 4.32 (s, 2 H, NCH2Ph),
7.21–7.28 (m, 5 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 24.2
(Me), 38.8 (CH2CH2Cl), 40.7 (CH2Cl), 44.4 (CH2), 60.8 (Cq), 72.8
(CH2O), 127.2, 127.8, 128.2 (CHAr), 137.7 (CqAr), 158.1 (CO)
ppm. HRMS: calcd. for C13H16ClNO2Na [M + Na]+ 276.0767;
found 276.0769.Compound 44 (190 mg, 19%) was also isolated by
ν
= 2979, 1735, 1219, 1064, 765, 699 cm–1. HRMS: calcd. for
˜
max
C17H24ClNO2Na [M + Na]+ 332.1229; found 332.1393.
Oxazolidinone 41: Yield: 513 mg, 50%. Purified by flash
1
flash chromatography. (PE/AcOEt, 75:25; Rf = 0.7). Oil. H NMR
chromatography (PE/AcOEt, 6:4; Rf = 0.4). M.p. 81 °C. [α]2D0
(200 MHz, CDCl3, 2 rotamers, 1:1 ratio): δ = 1.04 (d, J = 7.1 Hz, +8.6 (c = 0.8, CHCl3). H NMR (300 MHz, CDCl3): δ = 1.74 (d,
=
1
3 H, Me, one rotamer), 1.07 (d, J = 7.1 Hz, 3 H, Me, one rotamer),
J = 7.2 Hz, 3 H, Me), 1.81–1.92 (m, 2 H, CH2CH2Cl), 2.44–2.57
1.49–1.58 (m, 1 H, CHHCHMe), 1.89–1.96 (m, 1 H, CHHCHMe), (m, 1 H, CHHCl), 2.89–3.01 (m, 1 H, CHHCl), 3.91 (dt, J = 3.8,
2.25–2.28 (m, 1 H, CHMe), 3.27–3.36 (m, 2 H, NCH2), 4.49 (d,
part of AB syst., J = 14.8 Hz, 1 H, NCHHPh, one rotamer), 4.55
(d, part of AB syst., J = 14.8 Hz, 1 H, NCHHPh, one rotamer),
7.7 Hz, 1 H, 4-H), 5.18 (q, J = 7.2 Hz, 1 H, NCHMePh), 5.46 (d,
J = 7.6 Hz, 1 H, 5-H), 7.32–7.44 (m, 5 H, Ar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 18.2 (Me), 32.9 (CH2CH2Cl), 40.0 (CH2Cl),
Eur. J. Org. Chem. 2011, 794–801
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
799

F. Couty, B. Drouillat, F. Lemée
53.6, 56.2, 78.9 (CH), 126.3, 127.0, 127.2, 128.1, 128.7, 129.0 stirred at –78 °C for 50 min and then hydrolyzed by the addition
FULL PAPER
(CHAr), 134.0, 139.7 (CqAr), 157.4 (CO) ppm. IR (NaCl, film)
of aqueous saturated NH4Cl solution (5 mL). Addition of water
and AcOEt was followed by usual workup to give 180 mg of a 1:3
mixture of 33 and 47 (89%). An analytical sample of 47 was iso-
lated by preparative TLC (PE/AcOEt, 6:4); Rf = 0.8 (for 33) and
0.75 (for 47). 1H NMR (200 MHz, CDCl3): δ = 1.50–1.76 (m, 1 H,
CHHCH), 1.90–2.25 (m, 2 H, CH2CH), 2.60–2.80 (m, 1 H,
CHHCH), 4.02–4.23 (m, 1 H, CH2CHN), 4.20 (dd, J = 3.4, 8.8 Hz,
1 H, CHHO), 4.60 (dd, J = 8.0, 8.8 Hz, 1 H, CHHO), 4.91 (t, J =
5.2 Hz, 1 H, NCHPh), 7.19–7.33 (m, 5 H, Ar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 31.9, 35.7 (CH2), 59.8, 61.8 (CH), 67.7
(CH2O), 125.5, 127.2, 128.6 (CHAr), 142.4 (CqAr), 161.7 (CO)
ν
= 1746, 1405, 1200, 733, 699, 651 cm–1. HRMS: calcd. for
˜
max
C19H20ClNO2Na [M + Na]+ 352.1080; found 352.1085.
Oxazolidinone 42: Yield: 529 mg, 52%. Purified by flash
chromatography (PE/AcOEt, 8:2; Rf = 0.62). Oil. 1H NMR
(300 MHz, CDCl3): δ = 0.91 (t, J = 7.2 Hz, 3 H, Me), 1.22–1.75
(m, 6 H, CH2), 2.05 (q, J = 6.8 Hz, 2 H, CH2CH2Cl), 3.50 (br. t,
J = 6.7 Hz, 2 H, CH2Cl), 3.73 (q, J = 6.8 Hz, 1 H, 4-H), 4.10 (d,
part of AB syst., J = 15.3 Hz, 1 H, NCHHPh), 4.38–4.48 (m, 1 H,
5-H), 4.84 (d, part of AB syst., J = 15.3 Hz, 1 H, NCHHPh), 7.29–
7.36 (m, 5 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.9
(Me), 22.4, 27.9, 29.0, 30.6, 40.8 (CH2), 46.8 (CH), 55.0 (CH2),
77.9 (CH), 128.0, 128.9 (CHAr), 136.1 (CqAr), 158.1 (CO) ppm.
ppm. IR (NaCl, film): ν
= 2936, 1739, 1225, 1078, 1047,
˜
max
699 cm–1. HRMS: calcd. for C12H13NO2Na [M + Na]+ 226.0844;
found 226.0851.
IR (NaCl, film) ν
= 2955, 1740, 1413, 760, 700, 672 cm–1.
˜
max
HRMS: calcd. for C16H23ClNO2 [M + H]+ 296.1417; found
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectroscopic data for oxazolidinones 33–
296.1452.
37 and 39–43.
Oxazolidinone 43: Yield: 99 mg, 10%. Purified by flash chromatog-
raphy (PE/AcOEt, 50:50; Rf = 0.7). Oil. [α]2D0 = +12.3 (c = 0.3,
CHCl3). H NMR (300 MHz, CDCl3): δ = 1.35 (s, 3 H, Me), 1.39
(s, 3 H, Me), 1.65–1.71 (m, 2 H, CH2CH2Cl), 1.74 (d, J = 7.1 Hz,
Me), 3.29–3.34 (m, 2 H, CH2Cl), 3.67–3.72 (m, 1 H, 4-H), 5.09 (q,
J = 7.1 Hz, NCHMePh), 7.29–7.44 (m, 5 H, Ar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 16.6, 21.9, 28.3 (Me), 32.1 (CH2CH2Cl),
40.8 (CH2Cl), 51.9 (CH), 55.0, 60.1 (CH2), 80.0 (CqO), 126.9,
127.7, 128.6 (CHAr), 141.2 (CqAr), 157.3 (CO) ppm. HRMS:
calcd. for C15H20ClNO2Na [M + Na]+ 304.0932; found 304.1080.
1
Acknowledgments
Centre National de la Recherche Scientifique (CNRS) and Univer-
sity of Versailles St-Quentin-en-Yvelines are acknowledged for fin-
ancial support.
[1] D. A. Evans, J. Bartroli, T. L. Shih, J. Am. Chem. Soc. 1981,
103, 2127–2129.
Oxazolidinone 45: A suspension of 33 (162 mg, 0.676 mmol) and
sodium azide (219 mg, 3.38 mmol) in DMF (3 mL) was heated at
80 °C for 12 h. The reaction mixture was partitioned between water
and ethyl acetate. Usual workup gave an oil that was dried under
high vacuum to remove trace amounts of DMF and to afford 45
[2] D. A. Evans, A. S. Kim in Handbook of Reagents for Organic
Synthesis: Reagents, Auxiliaries and Catalysts for C–C Bond
Formation (Eds.: R. M. Coates, S. Denmark), Wiley, New York,
2000, pp. 91–101.
[3] M. R. Barbachyn, C. W. Ford, Angew. Chem. Int. Ed. 2003, 42,
1
as a clear oil (166 mg, 89%). Rf = 0.5 (PE/AcOEt, 1:1). H NMR
2010–2023.
[4] J. R. Gage, D. A. Evans, Org. Synth. Coll. Vol. 1993, VIII, 528–
531.
[5] J. B. Hyne, J. Am. Chem. Soc. 1959, 81, 6058–6061.
[6] A. K. Saund, B. Prashad, A. K. Koul, J. M. Bachhawat, N. K.
Marthur, Int. J. Peptide Protein Res. 1973, 5, 7–10.
[7] F. Applegath, US Patent 2857392, 1958 [Chem. Abstr. 1959, 53,
5286d].
(300 MHz, CDCl3): δ = 1.59–1.77 (m, 1 H, CHHCH2N3), 1.87–
2.02 (m, 1 H, CHHCH2N3), 3.30 (t, J = 6.6 Hz, 2 H, CH2N3),
3.60–3.75 (m, 1 H, 4-H), 4.01 (dd, J = 8.8, 6.6 Hz, 1 H, 5-H), 4.14
(d, J = 15.3 Hz, 1 H, NCHHPh), 4.36 (t, J = 8.7 Hz, 1 H, 5Ј-H),
4.72 (d, J = 15.3 Hz, 1 H, NCHHPh), 7.28–7.43 (m, 5 H, Ar) ppm.
13C NMR (75 MHz, CDCl3): δ = 30.3 (CH2CH2N3), 44.4 (CH2N3),
46.3 (NCH2Ph), 53.0 (CH), 67.3 (CH2O), 128.1, 128.2, 128.9
[8] For examples of oxazolidinones with a 4-bromoethyl or 4-
methanesufonyloxyethyl side chain, see inter alia: a) H. L.
Sham, H. Stein, J. Cohen, J. Chem. Soc., Chem. Commun. 1987,
1792–1793; b) A. Genevois-Borella, J.-C. Florent, C. Mon-
neret, D. S. Grierson, Tetrahedron Lett. 1990, 31, 4879–4882;
c) A. Tarnowski, T. Bär, R. R. Schmidt, Bioorg. Med. Chem.
Lett. 1997, 7, 573–576; d) D.-R. Hou, J. H. Reibenspies, K.
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(CHAr), 135.8 (CqAr), 158.3 (CO) ppm. IR (NaCl, film) ν
=
˜
max
2926, 2094, 1739, 1417, 1090, 1025, 701 cm–1. HRMS: calcd. for
C12H14N4O2Na [M + Na]+ 269.1014; found 269.1002.
Oxazolidinone 46: A solution of 33 (100 mg, 0.42 mmol) and potas-
sium cyanide (136 mg, 2.1 mmol) in DMSO (3 mL) was heated at
110 °C for 1 h. The reaction mixture was partitioned between water
and ethyl acetate. Usual workup gave a crude oil that was purified
by chromatography to give 46 (66 mg, 66%) as a clear oil. Rf =
0.15 (PE/AcOEt, 6:4). 1H NMR (300 MHz, CDCl3): δ = 1.72–1.90
(m, 1 H, CHHCH2CN), 1.87–2.05 (m, 1 H, CHHCH2CN), 2.29 (t,
J = 6.6 Hz, 2 H, CH2CN), 3.72–3.79 (m, 1 H, 4-H), 4.02 (dd, J =
8.8 and 6.6 Hz, 1 H, 5-H), 4.17 (d, J = 15.4 Hz, 1 H, NCHHPh),
4.39 (t, J = 8.7 Hz, 1 H, 5Ј-H), 4.72 (d, J = 15.4 Hz, 1 H,
NCHHPh), 7.28–7.39 (m, 5 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3): δ = 12.2 (CH2CH2CN), 27.4 (CH2N3), 53.4 (NCH2Ph),
60.4 (CH), 66.2 (CH2O), 119.3 (CN), 128.1, 128.3, 129.1 (CHAr),
135.4 (CqAr), 158.1 (CO) ppm. IR (NaCl, film) νmax = 2926, 2246,
˜
1737, 1419, 1244, 1090, 1031, 702 cm–1. HRMS: calcd. for
C13H14N2O2Na [M + Na]+ 253.0831; found 253.0953.
Oxazolidinone 47: To a solution of 33 (240 mg, 1 mmol) in THF
(10 mL) cooled to –78 °C was added dropwise a solution of nBuLi
(1.6 m in hexanes, 0.875 mL, 1.4 mmol). The reaction mixture was
800
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Eur. J. Org. Chem. 2011, 794–801

Ring Expansion of 2-(1-Hydroxyalkyl)azetidines
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Eur. J. Org. Chem. 2011, 794–801
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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