Convenient synthesis of oxazolidinones and oxazinones from allyl and homoallyl amines under mild conditions

Article abstract of DOI:10.1080/00397910600773890

An efficient one-pot general method for the high-yield synthesis in solution of oxazolidinones and oxazinones from allyl- and homoallylamines, respectively, has been developed. The reaction is carried out at an atmospheric pressure between 0°C and room te

Full text of DOI:10.1080/00397910600773890

This article was downloaded by: [Fordham University]
On: 18 March 2013, At: 10:33
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Convenient Synthesis of Oxazolidinones and
Oxazinones from Allyl and Homoallyl Amines
under Mild Conditions
a
a
a
Eduardo García‐Egido , Isabelle Fernández & Luis Muñoz
a
Department of Organic Chemistry, Faculty of Chemistry, University of Vigo,
Vigo, Spain
Version of record first published: 16 Feb 2007.
To cite this article: Eduardo García‐Egido , Isabelle Fernández & Luis Muñoz (2006): Convenient Synthesis
of Oxazolidinones and Oxazinones from Allyl and Homoallyl Amines under Mild Conditions, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:20,
3029-3042
To link to this article: http://dx.doi.org/10.1080/00397910600773890
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the
contents will be complete or accurate or up to date. The accuracy of any instructions, formulae,
and drug doses should be independently verified with primary sources. The publisher shall not
be liable for any loss, actions, claims, proceedings, demand, or costs or damages whatsoever or
howsoever caused arising directly or indirectly in connection with or arising out of the use of this
material.

w
Synthetic Communications , 36: 3029–3042, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600773890
Convenient Synthesis of Oxazolidinones and
Oxazinones from Allyl and Homoallyl
Amines under Mild Conditions
Eduardo Garc ´ı a-Egido, Isabelle Fern a´ ndez, and Luis Mu n˜ oz
Department of Organic Chemistry, Faculty of Chemistry,
University of Vigo, Vigo, Spain
Abstract: An efficient one-pot general method for the high-yield synthesis in solution
of oxazolidinones and oxazinones from allyl- and homoallylamines, respectively, has
been developed. The reaction is carried out at an atmospheric pressure between 08C and
room temperature using a solution of carbon dioxide in acetonitrile and hindered
guanidine as the base.
Keywords: Carbon dioxide, iodine, oxazinones, oxazolidinones
Oxazolidin-2-ones and oxazin-2-ones are important classes of heterocyclic
compounds containing five- and six-membered rings, respectively. The use
of enantiomerically pure oxazolidinones as chiral auxiliaries was first intro-
duced by Evans in 1981 (available from amino alcohols, which in turn are
[1]
readily obtained from amino acids or norephedrine). Several modifications
[2]
were subsequently introduced by the groups of Hinterman and Bull. As a
result, these systems have been widely used in asymmetric synthesis for the
preparation of enantiopure molecules. Thus, remarkable diastereoselectivity
in alkylation, acylation, aldol condensation, conjugate addition, and Diels–
[3]
Alder reactions could be obtained using such oxazolidinones in solution.
Nowadays, the emergence of solid-phase synthesis and combinatorial
[4]
chemistry has led to these systems being used as supported chiral auxiliaries.
Received in Poland January 18, 2006
Address correspondence to Luis Mu n˜ oz, Department of Organic Chemistry, Faculty
of Chemistry, University of Vigo, 36310 Vigo, Spain. E-mail: lmunoz@uvigo.es
3
029

3
030
E. Garc ´ı a-Egido, I. Fern a´ ndez, and L. Mu n˜ oz
In addition, the oxazolidin-2-one ring is present in numerous natural and
synthetic molecules with significant biological activity. This ring is also a
component of a novel class of synthetic antimicrobial agents with activity
against multidrug-resistant Gram-positive bacteria. Although these
compounds were initially discovered by researchers at DuPont in the late
1980s (DuP 721), researchers at Pharmacia Corporation finally identified
two clinical candidates, eperezolid and linezolid, with the latter being
w
approved by the US Food and Drug Administration (FDA) in 2000 (Zivox ).
[5]
Although a few methods have been published in the literature for the
synthesis of oxazolidinones, only two papers have been published studying
the synthesis of 5-substituted oxazolidin-2-ones using carbon dioxide
(
CO )—a reagent in which we are especially interested—and unsaturated
2
amines. The first example involved the synthesis of iodooxazolidinones and
iodooxazinones from allylamines and homoallylamines, respectively. The
reaction was carried out in solution with dissolved CO , using either a large
2
excess of the amine or caesium carbonate to generate the carbamate anion
in the basic medium. Iodine was subsequently added to the reaction
mixture. However, this method has important drawbacks because the yields
[6]
are low and the reaction times are very long.
The second article deals with a mechanistically similar one-step solid-
phase procedure leading to 5-(iodomethyl)oxazolidin-2-ones from allylic
amine hydrochlorides or free amines by reacting the allyl amine with the
reagent obtained by adsorbing iodine onto the resin Amberlyst A 26 in the
2
3
–
[7]
CO form.
In recent times, the nucleophilic reactivity of carbamate anions has been
[
8]
studied. These carbamate anions were prepared from an amine using carbon
dioxide and different bases. Among these bases, several hindered guanidines
proved to be very efficient reagents. On the basis of our experience in the use
of carbon dioxide as a reagent and the existing precedents in the literature, we
developed efficient reaction conditions for the nucleophilic opening of
iodonium ions by carbamate anions in solution.
Although weak bases such as amines or alkaline carbonates have been
used previously, giving poor yields, the use of strong bases is recommended
to shift the equilibrium between carbon dioxide and an amine to the
carbamate anion. Guanidines have proved to be among the best choices, not
[
9]
only because of their basicity but also because of the ability of the guanidi-
[
10]
nium ion to stabilize bidentate anions such as carbamates.
was used as the solvent because guanidines behave as strong bases in aceto-
Dry acetonitrile
[
11]
nitrile.
In addition, the solubility of carbon dioxide in acetonitrile is
rather high, thus ensuring a sufficiently high concentration of carbon
dioxide in the reaction medium at atmospheric pressure.
The nonnucleophilic guanidines 2-phenyl-1,1,3,3-tetramethylguanidine
(
have previously been used as bases in the alkylation of carbamate anions
PhTMG 1) and 2-cyclohexyl-1,1,3,3-tetramethylguanidine (CyTMG 2)
[
8]
with electrophiles. Because both guanidines—PhTMG (1) and CyTMG

Oxazolidinone and Oxazinone Synthesis
3031
(2)—are noncommercial reagents, we prepared them by a slight modification
of Bredereck’s procedure, replacing benzene with toluene as the solvent.
[12]
Thus, preparation of the Vilsmeier salt of tetramethylurea and subsequent
reaction with aniline and cyclohexylamine gave PhTMG and CyTMG in
8
7–98% and 46% yield, respectively. In our hands, PhTMG was obtained
in a much higher yield than reported in the literature (52%), whereas
CyTMG was obtained in moderate yield. An additional advantage of these
bases is that at pH , 10 they are present in solution as guanidinium cations
and are water soluble, whereas at pH 14 they are in the neutral form and
can be recovered from an organic solution.
The reaction conditions were adjusted using commercial allylamine (3a)
and diallylamine (3b) as substrates (Scheme 1, Table 1). To maintain the
maximum concentration of carbon dioxide in solution, several attempts
were made to prepare the initial solution by bubbling in carbon dioxide
between 220 and 08C. It was found that the optimal conditions were initial
saturation of the solution with carbon dioxide at 08C followed by stirring
under a carbon dioxide atmosphere.
The reaction was carried out using Na CO , PhTMG, and CyTMG as the
2
3
bases. Once the mixture of amine, base, and carbon dioxide in acetonitrile
had been prepared, a solution of iodine in acetonitrile was added. Sodium
carbonate proved to be very inefficient. Even after several days, the yields
were very low (ca. 17%). In contrast, both guanidines behaved similarly,
yielding the products in good to excellent yields in a few hours. Finally,
PhTMG was selected as the base because it was obtained in higher yield.
The time and scope of the reaction was studied with a set of different
allyl- and homoallylamines 3. Several of these compounds were commercially
available, and those that were not available were easily prepared by
monoalkylation of primary amines with alkyl halides. The results of the
reactions carried out with amines 3 according to Scheme 1 for different
times are shown in Table 1.
The reaction seems to be rather fast, although it takes some time to reach
completion. Within a few hours most of the product is formed, but the isolated
yields increase until they are nearly quantitative when the reaction time
approaches 1 day (entries 7, 8, and 9).
In general, reaction yields are very good with both primary and secondary
amines. In addition, oxazolidinones, and oxazinones 4 are stable solids, and
Scheme 1.

3
032
E. Garc ´ı a-Egido, I. Fern a´ ndez, and L. Mu n˜ oz
Table 1. Outcome for Scheme 1 reaction
Entry
Amine
n
Time (h) Yield (%) Product
1
2
3
1
2
3
4
5
6
7
8
9
3a R ¼ R ¼ R ¼ H
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
18
3
67
87
90
0
4a
4b
4b
4c
4d
4d
4e
4e
4e
4f
1
3
2
3b R ¼ R ¼ H, R ¼ CH
2
CH:CH
CH:CH
2
2
1
3
2
3b R ¼ R ¼ H, R ¼ CH
2
20
216
5
1
3
2
3c R ¼ R ¼ H, R ¼ Ph
1
3
2
3d R ¼ R ¼ H, R ¼ Bn
89
92
90
93
98
91
97
76
84
93
86
0
1
3
2
3d R ¼ R ¼ H, R ¼ Bn
18
2
1
3
2
3e R ¼ H, R ¼ CH
3
, R ¼ Et
1
3
2
3e R ¼ H, R ¼ CH , R ¼ Et
5
20
3
1
3
2
3e R ¼ H, R ¼ CH
3
, R ¼ Et
1
3
2
1
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
9
3f R , R ¼ 2(CH
2
)
4
–, R ¼ Bn
0.3
1
3
2
3f R , R ¼ 2(CH ) –, R ¼ Bn
16
2
4f
2
4
3
1
2
3g R ¼ H, R ¼ CH
3
, R ¼ Bn
4g
4g
4g
4h
4i
3
1
2
3g R ¼ H, R ¼ CH
3
, R ¼ Bn
5
3
1
2
3g R ¼ H, R ¼ CH , R ¼ Bn
20
20
24
2
3
3
1
2
3h R ¼ H, R ¼ Ph, R ¼ Bn
1
2
3
3i R , R ¼ 2(CH
2
)
2
–, R ¼ H
1
3
2
3j R , R ¼ 2(CH
2
)
4
–, R ¼ H
51
70
94
4j
1
3
2
3j R , R ¼ 2(CH ) –, R ¼ H
5
21
4j
2
4
1
3
2
3j R , R ¼ 2(CH
2
)
4
–, R ¼ H
4j
by-products are not generally found in the reaction mixture—although one
exception was found. Initially, the reaction with allylamine (3a) gave rather
poor yields (ca. 65%) due to losses in the workup resulting from the high
solubility of the oxazolidinone (4a) in water. The yield could be increased
to nearly 80% with a careful extraction in the workup. Nevertheless, two sub-
strates did not give any product. Allylaniline (3c) was recovered unreacted
after more than 1 week. This result clearly indicates that the low nucleophili-
city of anilines in comparison with amines precludes the formation of the
carbamate anion. It is more difficult to explain the low reactivity of 1,2,3,6-
tetrahydropyridine (3i). In this case, the high energy needed to overcome
the ring tension probably disfavors formation of the bicycle.
The reaction was found to be regioselective in all cases. Thus, with ally-
lamines and homoallylamines, only five- and six-membered rings were
obtained, respectively. Although the formation of the smaller possible ring
can be easily rationalized in entropic terms, the factors affecting the
reaction seem to be a bit more complex. When the reaction was carried out
with allylhomoallylamines, a more detailed picture of the reaction was
obtained. For example, substrate 5 gave an oxazolidinone–oxazinone ratio
of 1:2.4, whereas compound 6 reversed the ratio to 3:1 (Scheme 2). This
result clearly shows that ring size is not the only driving force in the reaction.
Further experiments are clearly needed in this area, but a possible expla-
nation for this behavior can be given by considering the reaction mechanism

Oxazolidinone and Oxazinone Synthesis
3033
Scheme 2.
in more detail. In this type of reaction, as in other additions of halogens to
alkenes, a halonium ion is postulated as an intermediate. It has been shown
that reactivity increases with additional substitution of electron-releasing
alkyl groups at the double bond. Thus, the outcome of the reaction can be
predicted in that the most substituted alkene will react to form the smaller
urethane ring.
Further evidence for the existence of an iodinium ion as an intermediate
is provided by the stereochemistry of the resulting oxazolidinones and oxazi-
nones. Only one diastereoisomer was obtained in all but one case. Entry 15
shows that reaction of N-benzyl-N-trans-cinnamylamine (3h) initially gave
a 1:1 mixture of epimeric oxazolidinones anti and syn 4h together with
small amounts of elimination products 11 (Scheme 3).
Because the epimerization of alkyl iodides in the benzylic position in the
presence of iodide ions is known, the reaction was repeated with the addition
of silver oxide to remove iodide ions from the reaction medium. Under such
conditions, only one diastereoisomer (anti-4h) was obtained along with a
small amount of elimination product E-11, with the amount of the latter
proportional to the reaction time. Once it had been demonstrated that in all
cases only a single diastereomer is the initial result of the reaction, the
stereochemistry had to be assigned.
Scheme 3.

3
034
E. Garc ´ı a-Egido, I. Fern a´ ndez, and L. Mu n˜ oz
In monocyclic oxazolidinones, the stereochemistry could be deduced
indirectly from the elimination product. This elimination reaction can be
assumed to be anti because only a single elimination product is obtained.
Thus, the stereochemistry of olefin 11, obtained as a single elimination
product when silver oxide was used, can readily be derived from nuclear Over-
hauser effect (NOE) experiments. The existence of a homonuclear NOE
between the H-4 methylenic protons of the oxazolidinone ring and the ortho
protons of the benzene ring identifies the double bond of compound 11 as E.
This alkene can only be obtained from the oxazolidinone resulting from anti
addition to the allylamine. This result is in complete agreement with the stereo-
chemistry of the electrophilic addition of halogens to double bonds.
Bicyclic oxazolidinones also provided evidence for the anti addition to
the double bond. A full structural and conformational analysis of compound
4f was performed in several solvents. Both homonuclear NOE correlations
and H NMR coupling constant analysis unambiguously indicated the anti
1
[13]
relative stereochemistry between iodine and oxygen.
1
The oxazinones obtained were also shown to be anti. H NMR data
were only compatible with the proposed stereochemistry. In addition,
single-crystal X-ray analysis of compound 4j confirmed the relative
[
14]
stereochemistry.
EXPERIMENTAL
IR spectra were obtained on a Bruker Vector 22 FTIR spectrophotometer.
Mass spectra were obtained on a Fisons VG Autospec M system. NMR
spectra were obtained on either a Bruker ARX400 or a Bruker Avance
DPX400 spectrometer. NMR spectra were recorded in deuterochloroform,
and the chemical shifts are expessed in parts per million (ppm) (d) relative
1
13
to the residual solvent signal (CDCl 7.27 for H and CDCl 77.00 for C).
3
3
[15]
2-Phenyl-1,1,3,3-tetramethylguanidine (PhTMG) (1)
A solution of phosphorus oxychloride (11.5 g, 7 mL, 0.075 mmol, 150 mol%)
in dry toluene (10 mL) was slowly added to a solution of 1,1,3,3-tetramethy-
lurea (5.81 g, 6 mL, 0.05 mmol, 100 mol%) in dry toluene (50 mL) under an
Ar atmosphere at 08C. The mixture was allowed to warm up to room tempe-
rature and stirred for 8 h. A solution of aniline (6.83 mL, 6.99 g, 75 mmol,
150 mol%) in dry toluene (20 mL) was slowly added at r.t. The mixture was
stirred at r.t. for 30 min and heated under reflux for 8 h. The phases were
separated. The oily phase (lower) was washed with toluene (3 ꢀ 10 mL) and
cooled to 08C. The pH was adjusted to 7–9 with 2 M NaOH, and the phase
was washed with EtOAc/hexane (1:1, 2 ꢀ 25 mL). At 08C, the aqueous
phase was basified with 4 M NaOH until pH . 14, and the white precipitate

Oxazolidinone and Oxazinone Synthesis
3035
was filtered off and discarded. The aqueous phase was extracted with EtOAc/
hexane (1:1, 4 ꢀ 40 mL), and the combined organic phases were dried with
anhydrous Na SO and concentrated under reduced pressure to give PhTMG
2
4
(
1) as a pale pink oil (8.250–9.270 g, 87–98%).
1
H NMR (400 MHz, CDCl ): d 7.14 (td, J ¼ 7.2 and 1.7 Hz, 2 H), 6.77
3
(
tt, J ¼ 7.3 and 1.1 Hz, 1 H), 6.65 (dd, J ¼ 8.3 and 1.1 Hz, 2 H), 2.64
1
br s, 12 H) ppm; C NMR (100 MHz, CDCl ): d 159.80 (s), 151.68 (s),
3
(
3
1
nmax 3071, 3056, 3006, 2924, 2885, 1604, 1576, 1506, 1377, 1139,
28.52 (d), 121.48 (d), 119.53 (d), 39.60 (q), 39.42 (q) ppm; FTIR (neat):
2
1
þ
1
108 cm ; MS (EI): m/e (relative intensity) 191 (M , 51), 176 (17), 147
100), 132 (39), 120 (24), 77 (14), 72 (18); HRMS (EI): calcd. for
(
C H N 191.1422 (M ), found 191.1432.
þ
1
1 17 3
2
-Cyclohexyl-1,1,3,3-tetramethylguanidine (2)
CyTMG was synthesized in a similar way to PhTMG (1) using 1,1,3,3-tetra-
methylurea (5.81 g, 6 mL, 0.05 mmol, 100 mol%), phosphorus oxychloride
(11.5 g, 7 mL, 0.075 mmol, 150 mol%), and cyclohexylamine (8.6 mL,
7
as a pale yellow oil (4.478 g, 46%). H NMR (400 MHz, CDCl ): d 3.11
.44 g, 75 mmol, 150 mol%) in dry toluene (80 mL). CyTMG was obtained
1
3
(
m, 1 H), 2.70 (s, 6 H), 2.64 (s, 6 H), 1.71 (m, 2 H), 1.57–1.55 (m, 3 H),
.28–1.24 (m, 5 H).
1
General Procedure for the Preparation of Oxazolidinones
and Oxazinones
CO was bubbled through an ice-cooled solution of the amine and PhTMG
2
(100–150 mol%) in acetonitrile for 10 min. Solid iodine (100–120 mol%)
was added in one portion to the solution, and CO was bubbled for an
2
additional period of 10 min. The temperature was allowed to rise to room
temperature, and the mixture was stirred for the given time, in the dark,
under a CO atmosphere. The solvent was removed under reduced pressure,
2
and the crude product was dissolved in EtOAc. The organic phase was
washed with 5% HCl and then with 10% NaHSO , dried with anhydrous
3
Na SO , filtered, and concentrated under reduced pressure. PhTMG can be
2
4
recovered from the aqueous phase.
5
-Iodomethyl-oxazolidin-2-one (4a)
According to the general procedure, to a solution of allylamine (0.150 mL,
.0 mmol) and PhTMG (1) (0.479 g, 2.5 mmol) in acetonitrile (30 mL), I2
0.508 g, 2.0 mmol) was added. After 18 h, the appropriate workup, and
2
(

3
036
E. Garc ´ı a-Egido, I. Fern a´ ndez, and L. Mu n˜ oz
chromatography (EtOAc/hexane 1:4 to 2:1), compound 4a was obtained as a
white crystalline solid (0.303 g, 67%).
1
Rf ¼ 0.5 (EtOAc); mp ¼ 117–1188C; H NMR (400 MHz, CDCl ): d
3
6
.37 (br s, 1 H), 4.73 (m, 1 H), 3.78 (t, J ¼ 8.8 Hz, 1 H), 3.43–3.38
1
3
(
CDCl ): d 159.18 (s), 75.13 (d), 46.36 (t), 5.83 (t); FTIR (KBr): n
m, 2 H), 3.31 (dd, J ¼ 10.3 and 8.4 Hz, 1 H); C NMR (100 MHz,
1782,
3 max
2
1
þ
1
6
2
2
734, 1244, 1097, 959 cm ; MS (EI): m/e (relative intensity), 227 (M ,
4), 127 (7), 100 (100), 86 (38); HRMS (EI): calcd. for C H INO
2
4
6
þ
26.9443 (M ), found 226.9444; Anal. calcd. for C H INO : C, 21.16; H,
4
6
2
.66; N, 6.17; O, 14.10; found C, 20.90; H, 2.34; N, 6.55.
3-Allyl-5-iodomethyl-oxazolidin-2-one (4b)
According to the general procedure, to a solution of diallylamine (0.248 mL,
.0 mmol) and PhTMG (1) (0.536 g, 2.8 mmol) in acetonitrile (30 mL), I2
0.508 g, 2.0 mmol) was added. After 20 h, the appropriate workup, and
2
(
chromatography (EtOAc/hexane 1:9 to 1:4), compound 4b was obtained as
a yellow oil (0.477 g, 90%).
1
Rf ¼ 0.38 (EtOAc/hexane 1:2); H NMR (400 MHz, CDCl ): d 5.72
3
(
(
m, 1 H), 5.29–5.24 (m, 2 H), 4.57 (m, 1 H), 3.86–3.84 (m, 2 H), 3.66
t, J ¼ 8.9 Hz, 1 H), 3.33 (dd, J ¼ 10.4 and 7.6 Hz, 1 H), 3.25 (dd, J ¼ 10.4
1
3
and 4.1 Hz, 1 H), 3.20 (dd, J ¼ 9.2 and 6.2 Hz, 1 H); C NMR (100 MHz,
CDCl ): d 156.64 (s), 131.41 (d), 118.78 (t), 71.43 (d), 49.65 (t), 46.55 (t),
3
2
1
6.75 (t); FTIR (KBr): n 1751, 1445, 1255 cm ; MS (EI): m/e (relative
max
intensity), 267 (M , 82), 140 (100), 127 (12), 96 (90), 82 (11), 68 (49);
þ
þ
HRMS (EI): calcd. for C H INO 266.9756 (M ), found 266.9743.
2
7
10
3-Benzyl-5-iodomethyl-oxazolidin-2-one (4d)
According to the general procedure, to a solution of N-allyl-N-benzylamine
3d) (0.300 g, 2.04 mmol) and PhTMG (1) (0.512 g, 2.68 mmol) in aceto-
nitrile (30 mL), I (0.568 g, 2.24 mmol) was added. After 18 h, the appropriate
(
2
workup, and chromatography (EtOAc/hexane 1:9 to 1:4), compound 4d was
obtained as a brown oil (0.592 g, 92%).
1
Rf ¼ 0.40 (EtOAc/hexane 1:2); H NMR (400 MHz, CDCl ): d 7.38–
3
7
.27 (m, 5 H), 4.53 (m, 1 H), 4.46 (d, J ¼ 14.9 Hz, 1 H), 4.36
(
d, J ¼ 14.9 Hz, 1 H), 3.54 (t, J ¼ 8.9 Hz, 1 H), 3.33 (dd, J ¼ 10.3 and
4
.1 Hz, 1 H), 3.23 (dd, J ¼ 10.3 and 7.9 Hz, 1 H), 3.14 (dd, J ¼ 8.9 and
3
1
.2 Hz, 1 H); C NMR (100 MHz, CDCl ): d 157.04 (s), 135.18 (s), 128.73
3
6
(
(
d), 128.05 (d), 127.95 (d), 70.59 (d), 49.58 (t), 48.11 (t), 6.50 (t); FTIR
2
1
neat): nmax 1754, 1445, 1253, 1089, 699 cm ; MS (EI): m/e (relative
þ
intensity) 317 (M , 13), 190 (94), 146 (25), 132 (14), 91 (100), 77 (5), 65
þ
(
18); HRMS (EI): calcd. for C H INO 316.9913 (M ), found 316.9906.
12
1
1
2

Oxazolidinone and Oxazinone Synthesis
-Ethyl-5-methyl-5-iodomethyl-oxazolidin-2-one (4e)
3037
3
According to the general procedure, to a solution of N-ethyl-2-methylallyla-
mine (0.264 mL, 2.00 mmol) and PhTMG (1) (0.505 g, 2.64 mmol) in aceto-
nitrile (30 mL), I (0.530 g, 2.08 mmol) was added. After 20 h, the appropriate
2
workup, and chromatography (EtOAc/hexane 1:5 to 1:1), compound 4e was
obtained as a white crystalline solid (0.515 g, 98%).
1
Rf ¼ 0.10 (EtOAc/hexane 1:4); mp ¼ 39–408C; H NMR (400 MHz,
CDCl ): d 3.44 (d, J ¼ 8.9 Hz, 1 H), 3.33 (d, J ¼ 10.6 Hz, 1 H), 3.28–3.20
3
1
3
(
m, 4 H), 1.56 (s, 3 H), 1.08 (t, J ¼ 7.1 Hz, 3 H); C NMR (100 MHz,
CDCl ): d 156.01 (s), 76.39 (s), 54.25 (t), 38.39 (t), 25.08 (q), 13.25 (t),
3
2
1
1
2.21 (q); FTIR (KBr): n
relative intensity), 269 (M , 92), 254 (28), 210 (16), 142 (12), 128 (100),
1748, 1300, 1054 cm ; MS (EI): m/e
max
þ
(
9
8 (11), 84 (23), 69 (41); HRMS (EI): calcd. for C H INO 268.9913
7
12
2
þ
M ), found 268.9900; Anal. calcd. for C H INO : C, 31.25; H, 4.50; N,
7 12 2
(
5
.21; O, 11.89; found C, 30.87; H, 4.33; N, 5.65.
ꢁ
ꢁ
ꢁ
(
2
3aR , 7R , 7aR )-3-Benzyl-7-iodo-hexahydrobenzoxazolidin-
-one (4f)
According to the general procedure, to a solution of (+)-N-(3-cyclohexenyl)-
N-benzylamine (3f) (0.379 g, 2.02 mmol) and PhTMG (1) (0.490 g,
2.56 mmol) in acetonitrile (30 mL), I2 (0.526 g, 2.07 mmol) was added.
After 16 h, the appropriate workup, and chromatography (EtOAc/hexane
1
:9 to 1:1), compound 4f was obtained as a white crystalline solid (0.698 g,
7%).
9
1
Rf ¼ 0.28 (EtOAc/hexane 1:1); mp ¼ 114–1158C; H NMR (400 MHz,
CDCl ): d 7.38–7.28 (m, 5 H), 4.70 (d, J ¼ 15.4 Hz, 1 H), 4.67 (t, J ¼ 6.3 Hz,
3
1
H), 4.32 (m, 1 H), 4.10 (d, J ¼ 15.4 Hz, 1 H), 3.68 (q, J ¼ 5.6 Hz, 1H), 2.11
1
3
m, 1 H), 1.92 (m, 1 H), 1.84–1.72 (m, 2 H), 1.54–1.39 (m, 2 H); C NMR
(
(
(
100 MHz, CDCl ): d 158.12 (s), 135.53 (s), 128.81 (d), 128.12 (d), 127.97
3
d), 79.41 (d), 53.57 (d), 45.92 (t), 32.92 (t), 26.46 (d), 24.71 (t), 20.09 (t);
2
1
FTIR (KBr): nmax 1748, 1396, 1042, 701 cm ; MS (EI): m/e (relative
þ
intensity), 357 (M , 5), 230 (9), 150 (61), 91 (100), 81 (40), 65 (7); HRMS
þ
(EI): calcd. for C H INO 357.0226 (M ), found 357.0224; anal. calcd.
for C H INO : C, 47.08; H, 4.52; N, 3.92; O, 8.96; found C, 47.45; H,
1
4
16
2
1
4
16
2
4
.12; N, 3.64.
ꢁ
0 ꢁ
(
5R ,1 S )-3-Benzyl-5-(1-iodoethyl)-oxazolidin-2-one (4g)
According to the general procedure, to a solution of N-benzyl-N-crotylamine
(
(
87:13 mixture of trans and cis) (3g) (0.161 g, 1.00 mmol) and PhTMG (1)
0.250 g, 1.31 mmol) in acetonitrile (25 mL), I (0.277 g, 1.09 mmol) was
2

3
038
E. Garc ´ı a-Egido, I. Fern a´ ndez, and L. Mu n˜ oz
added. After 20 h, the appropriate workup, and chromatography
(
(
EtOAc/hexane 1:9 to 1:4), compound 4g was obtained as a yellow solid
0.307 g, 93%).
1
Rf ¼ 0.33 (EtOAc/hexane 1:4); mp ¼ 42–438C; H NMR (400 MHz,
CDCl ): d (mixture of epimers 87:13) d 7.40–7.27 (m, 5 H), 4.52–4.34
3
(
m, 3 H), 4.16–4.02 (m, 1 H), 3.59–3.49 (m, 1 H), 3.26–3.16 (m, 1 H),
3
1
1
.96 (d, J ¼ 6.8 Hz, 2.6 H), 1.82 (d, J ¼ 7.0 Hz, 0.4 H);
C NMR
(
100 MHz, CDCl ): (major epimer) d 157.07, 135.17, 128.67, 127.97,
3
1
1
2
27.87, 76.72, 49.92, 48.01, 27.70, 23.47; FTIR (KBr): n
2
1756 (br),
þ
max
1
441, 1257, 702 cm ; MS (EI): m/e (relative intensity), 331 (M , 6),
04 (62), 150 (50), 106 (12), 91 (100), 69 (41); HRMS (EI): calcd.
þ
for C H INO 331.0069 (M ), found 331.0084; anal. calcd. for
1
2
14
2
C H INO : C, 43.52; H, 4.26; N, 4.23; O, 9.62; found C, 43.08; H, 3.87;
1
2
14
2
N, 4.64.
ꢁ
0 ꢁ
(5R , 1 S )-3-Benzyl-5-(1-iodobenzyl)-oxazolidin-2-one (anti-4h)
and (E)-3-Benzyl-5-(phenylmethylene)-2-oxazolidin-2-one ((E)-11)
According to the general procedure, to a solution of N-benzyl-N-trans-cinna-
mylamine (3h) (0.223 g, 1.00 mmol) and PhTMG (1) (0.205 g, 1.07 mmol) in
acetonitrile (25 mL), I (0.268 g, 1.06 mmol) and Ag O (0.237 g, 1.02 mmol)
2
2
were added. After 30 min, the crude product was filtered off (Celite), and the
appropriate workup and chromatography (EtOAc/hexane 1:9 to 1:3) gave
compound anti-4h as a white solid (0.237 g, 64%) and compound (E)-11 as
a white solid (0.003 g, 1%).
1
anti-4h: Rf ¼ 0.20 (EtOAc/hexane 1:3); mp ¼ 125–1268C; H NMR
(
400 MHz, CDCl ): d 7.41–7.28 (m, 10 H), 5.08 (d, J ¼ 7.7 Hz, 1 H), 4.98
3
(
td, J ¼ 8.5 and 7.2 Hz, 1 H), 4.48 (d, J ¼ 14.9 Hz, 1 H), 4.37
d, J ¼ 14.9 Hz, 1 H), 3.68 (t, J ¼ 8.8 Hz, 1 H), 3.35 (dd, J ¼ 9.2 and
(
1
.1 Hz, 1 H); C NMR (100 MHz, CDCl ): d 157.12 (s), 138.46 (s), 135.26
3
7
3
(
s), 129.02 (d), 128.93 (d), 128.89 (d), 128.80 (d), 128.24 (d), 128.13 (d),
28.11 (d), 128.07 (d), 75.81 (d), 50.33 (t), 48.25 (t), 33.38 (d); FTIR
1
2
1
(
KBr): n
1752, 1250, 712, 697 cm ; MS (EI): m/e (relative intensity),
max
þ
393 (M ), 266 (80), 130 (5), 117 (7), 91 (100); HRMS (EI): calcd. for
C H INO 393.0226 (M ), found 393.0253; anal. calcd. for C H INO :
þ
1
7
16
2
17 16
2
C, 51.93; H, 4.10; N, 3.56; O, 8.14; found C, 51.56; H, 4.57; N, 3.09.
1
(
E)-11: Rf ¼ 0.45 (EtOAc/hexane 1:3); H NMR (400 MHz, CDCl ): d
3
7
.42–7.18 (m, 7 H), 7.20 (t, J ¼ 7.4 Hz, 1 H), 7.04 (d, J ¼ 7.5 Hz, 2 H),
1
3
6
.30 (t, J ¼ 2.6 Hz, 1 H), 4.55 (s, 2 H), 4.33 (d, J ¼ 2.6 Hz, 2 H); C NMR
(
100 MHz, CDCl ): d 155.15, 144.12, 134.90, 133.72, 129.05, 128.77,
3
1
28.31, 128.09, 127.24, 126.69, 105.32, 48.00, 47.76; FTIR (KBr): n
max
2
770, 1684, 1243, 1061 cm ; MS (EI): m/e (relative intensity), 265 (M ,
1
þ
1
þ
47), 181 (16), 91 (100); HRMS (EI): calcd. for C H NO 265.1103 (M ),
found 265.1109.
1
7
15
2

Oxazolidinone and Oxazinone Synthesis
3039
ꢁ ꢁ
6R , 7S )-7-Iodo-1,3-oxazinespiro[5.5]undecane-2-one (4j)
(
According to the general procedure, to a solution of 2-(1-cyclohexenyl)-ethyl-
amine (0.280 mL, 2.00 mmol) and PhTMG (1) (0.511 g, 2.67 mmol) in aceto-
nitrile (30 mL), I (0.511 g, 2.01 mmol) was added. After 21 h, the appropriate
2
workup, and chromatography (EtOAc/hexane 1:1 to EtOAc), compound 4j
was obtained as a white crystalline solid (0.540 g, 94%).
1
Rf ¼ 0.28 (EtOAc); mp ¼ 147–1498C (lit. 150–1528C); H NMR
(
400 MHz, CDCl ): d 7.17 (br s, 1 H), 4.51 (t, J ¼ 4.3 Hz, 1 H), 3.38–3.25
3
(
m, 2 H), 2.30 (m, 1 H), 2.24–2.10 (m, 2 H), 2.05–1.92 (m, 2 H), 1.88–
1
3
1
.66 (m, 3 H), 1.60–1.50 (m, 2 H); C NMR (100 MHz, CDCl ): d 153.92
3
(s), 80.14 (s), 37.08 (d), 35.47 (t), 32.86 (t), 31.49 (t), 30.55 (t), 23.18 (t),
2
1
0.59 (t); FTIR (KBr): n
2
3237, 3125, 2935, 1698, 1371, 1248, 1112,
þ
max
1
002 cm ; MS (EI): m/e (relative intensity) 295 (M ), 168 (100), 150
(45), 125 (48),125 (49), 107 (20), 95 (33), 79 (16), 69 (19); HRMS (EI):
calcd. for C H INO 295.0069 (M ), found 295.0059; anal. calcd. for
þ
9
14
2
C H INO : C, 36.63; H, 4.78; N, 4.75; O, 10.84; found C, 36.45; H, 4.63;
9
14
2
N, 4.46.
3
-[2-(1-Cyclohexenyl)-ethyl]-5-iodomethyl-2-oxazolidinone (7) and
ꢁ ꢁ
(6R , 7S )-3-Allyl-7-iodo-1,3-oxazinespiro[5.5]undecane-2-one (8)
According to the general procedure, to a solution of N-allyl-N-2-(1-cyclo-
hexenyl)-ethylamine (5) (0.333 g, 2.02 mmol) and PhTMG (1) (0.430 g,
2
.25 mmol) in acetonitrile (30 mL), I2 (0.536 g, 2.11 mmol) was added.
After 20 h, the appropriate workup, and chromatography (EtOAc/hexane
:4 to 1:1), compound 7 was obtained as a yellow solid (0.149 g, 22%) and
compound 8 was obtained as a white solid (0.353 g, 52%).
1
1
7
: Rf ¼ 0.37 (EtOAc/hexane 1:2); mp ¼ 39–408C; H NMR (400 MHz,
CDCl ): d 5.47 (s, 1 H), 4.54 (m, 1 H), 3.65 (t, J ¼ 8.8 Hz, 1 H), 3.42–3.19
3
(
(
(
m, 5 H), 2.18 (t, J ¼ 6.9 Hz, 2 H), 1.97–1.95 (m, 4 H), 1.64–1.51
1
m, 4 H); C NMR (100 MHz, CDCl ): d 156.86 (s), 134.09 (s), 123.78
3
3
d), 71.69 (d), 49.88 (t), 41.83 (t), 35.75 (t), 27.67 (t), 25.22 (t), 22.70 (t),
2
1
2.20 (t), 6.35 (t); FTIR (KBr): n
2
2925, 1752 (br), 1439, 1261,
þ
max
1
018 cm ; MS (EI): m/e (relative intensity), 335 (M , 37), 240 (12), 228
(56), 196 (27), 108 (100), 93 (18), 79 (25); HRMS (EI): calcd. for
C H INO 335.0382 (M ), found 335.0382; anal. calcd. for C H INO :
þ
1
2
18
2
12 18
2
C, 43.00; H, 5.41; N, 4.18; O, 9.55; found C, 42.91; H, 5.23; N, 4.09.
1
8
: Rf ¼ 0.29 (EtOAc/hexane 1:2); mp ¼ 66–708C; H NMR (400 MHz,
CDCl ): d 5.74 (m, 1 H), 5.18–5.13 (m, 2 H), 4.41 (t, J ¼ 4.4 Hz, 1 H), 3.97–
3
3
.85 (m, 2 H), 3.22–3.14 (m, 2 H), 2.30–2.17 (m, 2 H), 2.13–1.42 (m, 8 H);
1
3
C NMR (100 MHz, CDCl ): d 152.02, 132.00, 117.92, 79.69, 51.27, 40.15,
3
3
7.29, 32.86, 31.45, 31.36, 23.21, 20.59; FTIR (KBr): n
2
2938, 1696, 1493,
þ
max
1
1
448, 1278, 1099 cm ; MS (EI): m/e (relative intensity) 335 (M , 66), 228

3
040
E. Garc ´ı a-Egido, I. Fern a´ ndez, and L. Mu n˜ oz
(
calcd. for C H INO 335.0382 (M ), found 335.0396; anal. calcd. for
20), 208 (62), 164 (42), 114 (77), 108 (81), 95 (64), 70 (100); HRMS (EI):
þ
1
2
18
2
C H INO : C, 43.00; H, 5.41; N, 4.18; O, 9.55; found C, 42.87; H, 5.07;
1
2
18
2
N, 4.45.
ꢁ
ꢁ
ꢁ
(
3aR , 7R , 7aR )-3-[2-(1-Cyclohexenyl)-ethyl]-7-iodo-hexahydro-
ꢁ
ꢁ
benzoxazolidin-2-one (9) and (6R , 7S )-3-(1-Cyclohexenyl)-7-iodo-
,3-oxazinespiro[5.5]undecane-2-one (10)
1
According to the general procedure, to a solution of (+) N-(3-cyclohexenyl)-
N-2-(1-cyclohexenyl)-ethylamine (6) (0.415 g, 2.01 mmol) and PhTMG (1)
(
0.410 g, 2.14 mmol) in acetonitrile (30 mL), I (0.525 g, 2.07 mmol) was
2
added. After 14 h, the appropriate workup and chromatography (EtOAc/
hexane 1:9 to 1:2), compound 9 was obtained as a white crystalline solid
(
0.475 g, 63%) and compound 10 was obtained as a brown oil (0.158 g, 21%).
1
9
: Rf ¼ 0.32 (EtOAc/hexane 1:4); mp ¼ 112–1138C; H NMR
(
400 MHz, CDCl ): d 5.45 (s, 1 H), 4.65 (t, J ¼ 6.1 Hz, 1 H), 4.34 (m, 1 H),
3
3
1
1
2
n
.86 (q, J ¼ 5.9 Hz, 1 H), 3.54 (m, 1 H), 3.01 (m, 1 H), 2.16–1.89 (m, 9 H),
1
.75–1.49 (m, 7 H); C NMR (100 MHz, CDCl ): d 157.55 (s), 134.19 (s),
3
3
23.66 (d), 79.19 (d), 53.61 (d), 40.11 (t), 35.84 (t), 32.59 (t), 28.02 (t),
6.58 (d), 25.21 (t), 25.03 (t), 22.76 (t), 22.19 (t), 20.19 (t); FTIR (KBr)
2
1
2929, 1749, 1396, 1015 cm ; MS (EI): m/e (relative intensity), 375
max
þ
(M , 78), 280 (21), 268 (58), 248 (21), 236 (18), 207 (54), 168 (22), 154
(58), 140 (17), 108 (97), 93 (24), 81 (97), 79 (100); HRMS (EI): calcd. for
þ
C H INO 375.0695 (M ), found 375.0701; anal. calcd. for C H INO :
2
1
5
22
2
15 22
C, 48.01; H, 5.91; N, 3.73; O, 8.53; found C, 47.64; H, 5.67; N, 3.24.
1
1
0: Rf ¼ 0.16 (EtOAc/hexane 1:4); H NMR (400 MHz, CDCl3):
(
(
(
(
(
mixture of rotamers) d 5.94 (m, 1 H), 5.47 (m, 1 H), 4.97 (m, 1 H), 4.47
1
3
q, J ¼ 4.8 Hz, 1 H), 3.34–3.09 (m, 2 H), 2.36–1.48 (m, 16 H); C NMR
100 MHz, CDCl ): (mixture of rotamers) d 152.46 (s), 132.40 (d), 132.34
3
d), 127.21 (d), 127.19 (d), 79.50 (s), 79.34 (s), 52.74 (d), 38.35 (d), 37.70
d), 35.88 (t), 35.85 (t), 33.26 (t), 32.99 (t), 32.32 (t), 31.99 (t), 31.92 (t),
2
6.02 (t), 25.92 (t), 24.53 (t), 23.55 (t), 23.23 (t), 21.19 (t), 21.16 (t), 21.02
2937, 1689 (br), 1428, 1293, 1180, 1102,
(
t), 20.73 (t); FTIR (neat) n
1
max
2
þ
7
53 cm ; MS (EI): m/e (relative intensity), 375 (M , 8), 248 (100), 204
(
HRMS (EI): calcd. for C H INO 375.0695 (M ), found 375.0699.
54), 176 (12), 168 (28), 140 (22), 109 (41), 96 (13), 81 (94), 67 (23);
þ
1
5
22
2
ACKNOWLEDGMENTS
L. M. thanks the Ministerio de Educaci o´ n (BQU2002-02807) and the Xunta de
Galicia (PGIDIT03PXIC30107PN) for financial support. E. G.-E. is grateful
to the Xunta de Galicia for a fellowship.

Oxazolidinone and Oxazinone Synthesis
REFERENCES
3041
1. Evans, D. A.; Bartroli, J.; Shih, T. L. Enantioselective aldol condensations; 2:
Erythro-selective chiral aldol condensations via boron enolates. J. Am. Chem.
Soc. 1981, 103, 2127–2129.
. (a) Hintermann, T.; Seebach, D. A useful modification of the Evans auxiliary:
2
4-Isopropyl-5,5-diphenyloxazolidin-2one. Helv. Chim. Acta 1998, 81,
2093–2126; (b) Bull, S. D.; Davies, S. G.; Jones, S.; Sanganee, H. J. Asymmetric
alkylations using SuperQuat auxiliaries—an investigation into the synthesis and
stability of enolates derived from 5,5-disubstituted oxazolidin-2-ones. J. Chem.
Soc., Perkin Trans. 1 1999, 387–398.
3
4
5
6
. Ager, D. J.; Prakash, I.; Schaad, D. R. 1,2-Amino alcohols and their heterocyclic deriva-
tives as chiral auxiliaries in asymmetric synthesis. Chem. Rev 1996, 96, 835–875.
. Chung, C. W. Y.; Toy, P. H. Chiral auxiliaries in polymer-supported organic
synthesis. Tetrahedron: Asymmetry 2004, 15, 387–399.
. Barbachyn, M. R.; Ford, C. W. Oxazolidinone structure–activity relationships
leading to linezolid. Angew. Chem. Int. Ed. 2003, 42, 2010–2023.
. Toda, T.; Kitagawa, Y. Use of carbon dioxide in organic synthesis via ammonium
carbamates, Part 8: Oxazolidines and oxazinones from allylamines and homoally-
lamines, carbon dioxide and iodine via intramolecular cyclization. Angew. Chem.
Int. Ed. Eng. 1987, 26, 334–335.
7
. Cardillo, G.; Orena, M.; Sandri, S. Oxazolidin-2-ones from allylic amines by
means of iodine and carbonate anion on polymeric support: A convenient
synthesis of (+)-propranolol. J. Org. Chem. 1986, 51, 713–717.
8
. (a) Belforte, A.; Calderazzo, F. Formation of alkylurethanes from carbon dioxide
by regioselective O-alkylation of alkali-metal N,N-diethylcarbamates in the
presence of complexing agents. J. Chem. Soc., Dalton Trans. 1989, 1007–1009;
(
b) McGhee, W. D.; Riley, D. P. Palladium-mediated synthesis of urethanes
from amines, carbon dioxide, and cyclic diolefins. Organometallics 1992, 11,
00–907; (c) Butcher, K. J. Carbamate esters: A simple, mild method of
9
formation. Synlett 1994, 825–826; (d) McGhee, W.; Riley, D.; Christ, K.;
Pan, Y.; Parnas, B. Carbon dioxide as a phosgene replacement: synthesis mechan-
istic studies of urethanes from amines. J. Org. Chem. 1995, 60, 2820–2830.
. Barton, D. H. R.; Elliot, J. D.; G e´ ro, S. D. Synthesis and properties of a series of
sterically hindered guanidine bases. J. Chem. Soc., Perkin Trans. 1 1982,
9
2085–2090.
1
0. Boyle, P. H.; Convery, M. A.; Davis, A. P.; Hosken, G. D.; Murray, B. A.
Deprotonation of nitroalkanes by bicyclic amidine and guanidine bases:
evidence for molecular recognition within a catalytic cycle for carbon–carbon
bond formation. J. Chem. Soc., Chem. Commun 1992, 239–242.
1
1
1
1. Leffek, K. T.; Pruszynski, P.; Thanapaalasingham, K. Basicity of substituted
2-phenyl-1,1,3,3-tetramethylguanidines and other bases in acetonitrile solvent.
Can. J. Chem. 1989, 67, 590–595.
2. Bredereck, H.; Bredereck, K. Acid amide reactions, XXVII: Reactions with acid
amide-phosphorus oxychloride adducts and amide chlorides. Chem. Ber. 1961,
94, 2278–2295.
3. Vaz, E.; Fern a´ ndez, I.; Mu n˜ oz, L. Llor J. Conformational equilibria of 7-benzyl-2-
iodo-9-oxa-7-azabicyclo[4.3.0]nonan-8-one in solution. Correlations between
conformational distribution and solvent solvatochromic parameters. J. Org.
Chem. 2006, 71, 2558–2564.

3
042
E. Garc ´ı a-Egido, I. Fern a´ ndez, and L. Mu n˜ oz
1
4. Garc ´ı a-Egido, E.; Marcos, M.; Carballo, R.; Mu n˜ oz, L. Structural and confor-
mational study of (+)-(6S,7R)-3-aza-7-iodo-1-oxaspiro[5,5]undecan-2-one.
J. Mol. Struct. 2000, 524, 233–239.
1
5. Mobinikhaledi, A.; Forughifar, N.; Mohtasabi, S.; Shalbaf, H. Synthesis of some of
new substituted 2-(phenyl)-1,3-dimethyl- and 1,1,3,3-tetramethylguanidines.
Phosphorus, Sulfur Silicon Relat. Elem. 2003, 178, 2235–2240.