An anomeric effect drives the regiospecific ring-opening of 1,3-oxazolidines under acetylating conditions

Article abstract of DOI:10.1002/ejoc.201000636

A series of oxazolidines derived from tris(hydroxymethyl)-aminomethane (TRIS; 1), have been prepared efficiently. Geometries optimized at the B3LYP/6-31G^* level of theory, along with the crystal data of compounds 9 and 12 and NOESY correlations

Full text of DOI:10.1002/ejoc.201000636

FULL PAPER
DOI: 10.1002/ejoc.201000636
An Anomeric Effect Drives the Regiospecific Ring-Opening of
1,3-Oxazolidines under Acetylating Conditions
R. Fernando Martínez,*[a] Martín Ávalos,[a] Reyes Babiano,[a] Pedro Cintas,[a]
José L. Jiménez,[a] Mark E. Light,[b] Juan C. Palacios,[a] and Esther M. S. Pérez[a]
Dedicated to Professor Vicente Ramos Estrada on the occasion of his retirement
Keywords: Heterocycles / Acylation / Regioselectivity / Anomeric effect
A series of oxazolidines derived from tris(hydroxymethyl)-
aminomethane (TRIS; 1), have been prepared efficiently.
Geometries optimized at the B3LYP/6-31G* level of theory,
along with the crystal data of compounds 9 and 12 and
NOESY correlations, point to a strong endo anomeric effect
that anchors a preferential conformation and subsequently
dictates the completely regioselective ring-opening of the ox-
azolidine moiety under acetylating conditions to afford im-
ines instead of N-acetyloxazolidines. This process was moni-
tored by 1H NMR spectroscopy, corroborated by synthesis,
and rationalized by the intermediacy of an iminium ion. Ox-
azolidine–imine equilibria are also described for TRIS and
other aminopolyols. The equilibria are shifted to the hetero-
cyclic partner as the number of reactive hydroxy groups in-
creases. The structures of an unprotected imine (31) and a
per-O-acetylated derivative (43) have also been established
by crystallographic analyses.
Introduction
This protocol, exemplified in Scheme 1 for the imine 6 (Ar
Recently, in the course of studies directed towards the = 2-HOC6H4) derived from a structurally simple amino-
preparation of chiral imines from amino sugars, we ob- polyol, tris(hydroxymethyl)aminomethane (usually abbrevi-
served the unexpected formation of N-acetyl-1,3-oxazolid- ated as TRIS; 1), and salicylaldehyde, points to an advan-
ines upon acetylation.[1] This transformation most likely oc- tageous synthesis of unprotected N-acetyloxazolidines (5)
curs via the transient formation of a chiral iminium ion.[2] with a significant atom economy relative to the previously
Scheme 1. Reagents and conditions: i) ArCHO (2 mol), C6H6, ∆; ii) CH3COCl; iii) H2O; iv) aqueous NaOH or NaHCO3; v) ArCHO
(1 mol); vi) Ac2O, C5H5N; vii) NH3, MeOH.
[a] Departamento de Química Orgánica e Inorgánica, QUOREX
described method (1Ǟ2Ǟ3Ǟ4Ǟ5)[3–5] that saves one mmol
of aldehyde.
Research Group, Facultad de Ciencias, Universidad de
Extremadura,
06071 Badajoz, Spain
In this paper we report in detail both the formation and
stereocontrolled ring-opening of 1,3-oxazolidines derived
from TRIS. As we shall see later, it is possible to identify
for such heterocycles a strong anomeric effect that dictates
their subsequent and regioselective conversion into imines.
View this journal online at
Fax: +34-924-271-149
E-mail: rmarvaz@unex.es
[b] Department of Chemistry, University of Southampton,
Highfield, Southampton, UK, SO17 1BJ
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000636.
wileyonlinelibrary.com
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R. F. Martínez et al.
FULL PAPER
The anomeric effect is a major stereoelectronic effect in Table 1. Selected bond lengths [Å], angles [°], and torsion angles [°]
for compounds 8, 9, and 12.
organic chemistry. Although theories on the ultimate origin
of this curious effect are invariably open, it has long been
held that both anomeric and anti-anomeric effects are re-
sponsible for conformational preferences in some heterocy-
9
12
8
X-ray Calcd.[a] X-ray Calcd.[a] Calcd.[a]
C4–C5
1.5490
1.4496
1.4779
1.4488
1.4382
1.5589
1.4677
1.4883
1.4242
1.4264
1.5570
1.4619
1.4885
1.4298
1.4394
1.5598
1.4671
1.4883
1.4231
1.4266
1.5591
1.4672
1.4885
1.4240
1.4266
105.037
104.436
104.101
105.469
106.423
178.12
cles and influence the stereochemical outcome of numerous N–C2
organic reactions.[6,7]
N–C4
O1–C2
O1–C5
C2–O1–C5
106.10 105.028 103.48 105.104
104.67 104.466 103.64 104.364
104.30 104.096 103.27 104.089
106.04 105.461 106.04 105.474
105.94 106.375 105.34 106.405
Results and Discussion
C2–N–C4
N–C4–C5
O1–C5–C4
O1–C2–N
Synthesis and Structural Assignment of TRIS-Based
Oxazolidines
H–N–C2–H2 161.50
160.83
170.21
161.42
In the search for environmentally friendly conditions, re- [a] Calculated at the B3LYP/6-31G* level of theory.
actions of TRIS with different monosubstituted benzalde-
hydes were attempted in water/methanol mixtures at room
temperature. However, only aldehydes bearing electron-
withdrawing groups led to products that were easily iso-
lated. Thus, instead of the expected imines, racemic mix-
tures of oxazolidines 8–16 were obtained.
The structures attributed to the above-mentioned sub-
stances are supported by spectroscopic and analytical data.
Moreover, suitable crystals for X-ray diffraction analysis
could be grown for oxazolidines 9 and 12 (see Figures 1 and
2).[8] Selected bond lengths, bond angles, and dihedral
angles for such derivatives are presented in Table 1. For
comparative purposes, empirical data are presented along
with theoretical figures obtained at the B3LYP/6-31G*
level.[9,10]
the 2-H proton (≈ 11 Hz). This value suggests a trans or
antiperiplanar disposition between these hydrogen atoms,
or, in other words, the hydrogen in NH adopts a pseudo-
axial orientation in solution.[11a] As evidenced by crystal
data, this disposition is also adopted in the solid state and
the dihedral angle H–N–C–H has a value of around 160°.
The oxazolidine ring exhibits a geometry consistent with
2
either E or E2 conformations in which the benzene ring
lies in an equatorial arrangement thereby avoiding its inter-
action with other substituents (see Figures 1 and 2).[11b]
The relative disposition between the 2-H and NH pro-
tons is likewise supported by NOEs determined by NOESY
correlations measured for compound 8 (Table S2 and Fig-
ure S1 in the Supporting Information).
Anomeric Effect in TRIS-Based Oxazolidines
This particular geometry of the oxazolidine ring could
have its origin in a strong endo anomeric effect.[6,7] Thus,
on the basis of MO theory, the equatorial lone-pair of the
nitrogen atom is placed in a favorable disposition to interact
with the σ* orbital of the C2–O1 bond, thus causing an
anomeric effect.[12,13] As a result of this interaction there is
delocalization of the lone-pair and a partial electron trans-
fer to the σ* orbital, which destabilizes the corresponding
σ-bonding orbital, thereby weakening the C2–O1 bond and
strengthening the C2–N bond. Overall, this translates into
a shorter C2–N bond and a longer C2–O1 bond. Similar
conclusions can be inferred from valence bond theory and
resonance effects, the greater stability of the conformer with
Figure 1. Experimental and calculated geometries for compound 9.
Figure 2. Experimental and calculated geometries for compound
12.
The spectroscopic data for compounds 8–16 have a diag- the NH in an axial disposition being accounted for by the
nostic value that rules out alternative isomeric structures. hyperconjugation in the canonical form 18 (Figure 3),
The FTIR spectra reveal stretching bands of the hydroxy which is consistent with a higher bond order for C2–N and
groups in the range of 3600–3000 cm–1 and of the NH ab- a lower one for C2–O1.
sorption at 3280–3250 cm–1, whereas no characteristic
It is true that the equatorial lone-pair on the oxygen
bands arising from an imine double bond are observed atom may also interact with the σ* orbital of the C2–N
above 1610 cm–1. The NMR spectra show resonances typi- bond, thus causing an opposite anomeric effect. However,
cal of the oxazolidine ring, for example, 2-H (≈ 5.5 ppm) had this effect been present, it would be weaker due to the
and C-2 (≈ 91 ppm; see Table S1 of the Supporting Infor- higher energy of the σ* orbital of the C2–N bond. That
mation).
delocalization would be less intense than that of the nitro-
The most salient structural feature manifests itself gen lone-pair; in other words, the nitrogen serves as donor
through the coupling constant between the NH group and and the oxygen as acceptor. This situation is reflected best
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Regiospecific Ring-Opening of 1,3-Oxazolidines
Figure 3. Anomeric effects in 1,3-oxazolidines.
by the delocalization shown in 18 and not in 19.[13,14] Sim-
The interaction between the nitrogen lone-pair (LPN) as
ilar conclusions have been proposed for other 1,3-oxazol- donor and σ*C2–O1 as acceptor (≈ 8.34 kcalmol–1) is much
idines[15] and 1,3-oxazanes.[16,17]
stronger than that of the O1 lone-pair (LPO1) as donor and
In summary, the anomeric effect is expected to result in σ*C2–N as acceptor (≈ 5.82 kcalmol–1).
a longer C2–O1 bond and a shorter C2–N bond relative to
Remarkably, the structures calculated for 8, 9, and 12
the regular C5–O1 and C4–N bonds that are not affected invariably show the NH group in an axial disposition with
by the anomeric effect.
a dihedral angle (H–N–C2–H2) of about 160–180°, which
A closer inspection of the X-ray data of 9 and 12 is similar to that determined experimentally (Table 1). We
(Table 1) reveals further support for the anomeric effect. were unable to locate a conformational minimum for the
Thus, the N–C2 bonds are significantly shorter (≈ 0.03 Å) NH group in an equatorial orientation.
than the corresponding distances for N–C4, which is consis-
Oxazolidine–Imine Equilibria
tent with the delocalization of the lone-pair on the nitrogen
(∆d = 0.0283 Å for 9 and ∆d = 0.0266 Å for 12). In con-
trast, the lengths of the C2–O1 bonds do not show any
significant variation capable of supporting an anomeric ef-
fect by delocalization of the lone-pair on oxygen (∆d =
–0.0106 Å for 9 and ∆d = 0.0096 Å for 12).
When [D6]DMSO solutions of compounds 8–16 were
kept at room temperature, a partial isomerization could be
detected (Scheme 2, Table 3, Figure S2) leading to a mix-
ture in which the starting oxazolidines are largely favored
(≈ 89–93%). Maiereanu et al.[15] have also reported an equi-
librium for 4-dimethylaminobenzylidene derivatives of
TRIS, although both tautomers are present in similar pro-
portions (≈ 1:1). The spectroscopic data for such equilibria
show the diagnostic resonances of the corresponding imines
Theoretical Calculations
DFT calculations at the B3LYP/6-31G* level of
theory[9,10] were also performed to evaluate the gas-phase
geometries of compounds 8, 9, and 12. The results were
compared with the crystal data (Table 1, Figures 1 and 2)
and showed quite good agreement with the calculated dis-
tances reproducing the anomeric effect and showing shorter
N–C2 bonds by about 0.02 Å (∆d = 0.0206 Å for 9 and ∆d
= 0.0212 Å for 8 and 12), although these variations are
slightly smaller than those measured experimentally.
The stabilization energies associated with nǞσ* elec-
tronic delocalizations were subsequently obtained from a
natural bond orbital (NBO) analysis based on the opti-
mized ground-state geometries of compounds 8, 9, and 12.
Table 2 shows selected donor–acceptor natural bond orbital
interactions and their second-order perturbational stabiliza-
tion energies, E2, calculated for the O1–C2–N fragment.
Scheme 2.
Table 3. Composition and NMR spectroscopic data for the imine
group in the oxazolidine–imine equilibria.
Table 2. Second-order perturbational energies from NBO analysis.
Equilibrium
Ratio [%] δ (N=CH) [ppm] δ (N=CH) [ppm]
Compound
Donor NBO
Acceptor NBO E2 [kcalmol–1][a]
8i20
93:7
91:9
93:7
90:10
91:9
92:8
89:11
91:9
89:11
57:43
50:50
57:43
17:83
8.55
8.50
8.51
8.50
8.54
8.45
8.50
8.45
8.80
8.48
8.42
8.59
8.45
157.66
158.20
158.57
158.89
157.93
157.91
158.80
157.68
153.61
157.05
157.73
156.81
155.61
8
LPN
LPO1
LPO1
σ*C2–O1
σ*C2–N
σ*C2–N
8.35
1.60
5.82
9i21
10i22
11i23
12i24
13i25
14i26
15i27
16i28
29i34
30i35
36i31
37i32
9
LPN
LPO1
LPO1
σ*C2–O1
σ*C2–N
σ*C2–N
8.32
1.60
5.82
12
LPN
LPO1
LPO1
σ*C2–O1
σ*C2–N
σ*C2–N
8.34
1.62
5.84
[a] Calculated at the B3LYP/6-31G* level of theory.
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R. F. Martínez et al.
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20–28: A singlet signal for the imine proton at around by fractional crystallization a pure diastereomer (30b) as a
8.50 ppm and a resonance for the unsaturated carbon at racemic mixture, which converted in DMSO solution into
around 158 ppm.
a mixture of 30a, 30b, and 35 in equilibrium (Scheme 3).
Because we wondered whether the formation of an ox-
azolidine ring would only occur with TRIS, condensation
reactions of 2-amino-2-methylpropane-1,3-diol with 4-ni-
trobenzaldehyde and methyl 4-formylbenzoate were also
studied. In these cases, the corresponding oxazolidines 29
and 30 were isolated in good yields. However, the reaction
of the aforementioned alcohol or 2-amino-2-methylpropan-
1-ol with 3-nitrobenzaldehyde gave rise to imines 31 and 32
in excellent yields. In addition, the imine derivative 33 was
obtained from 3-aminopropane-1,2-diol.
The configuration (2R,4R) [or (2S,4S) for its enantiomer]
attributed to 30a was established on the basis of a NOE
between the methyl hydrogens at C-4 and 2-H (Figure S3 in
the Supporting Information) measured in the equilibrium
mixture (30a/30b/35, 27:23:50).
Compound 33 was reluctant to undergo cyclization, al-
though after 2 weeks in solution four carbon signals ap-
peared in the range 92–86 ppm. Such resonances can be at-
tributed to two diastereomeric oxazolidines arising from cy-
clization of the secondary hydroxy (38, diastereomeric ratio
32:68) and to two oxazines resulting from cyclization of the
primary hydroxy (39, diastereomeric ratio 44:56). Neverthe-
less, the amount of cyclized products was less than 6% in
the whole mixture (33/38/39 = 94:4:2).
These results reveal that in such equilibria the percentage
of oxazolidines derived from aldehydes with electron-with-
drawing substituents increases on increasing the number of
available hydroxy groups: ≈20% for derivatives of 2-amino-
2-methylpropan-1-ol, ca. 60% for those of 2-amino-2-meth-
ylpropane-1,3-diol, and ca. 100% for those based on TRIS.
These percentages are related to the statistical probability
of cyclization with the number of hydroxy groups present.
The Hammett plot for logKring–chain (= [ring]/[chain])
against σ values gave a linear relationship although with a
rather poor fit (r = 0.62). Nevertheless, the negative value
of ρ (–0.35) suggests that electron-withdrawing substituents
favor oxazolidine formation.
The NMR spectroscopic data for compounds 29 and 30
show similar chemical shifts to those of 8–16 (doublet at
5.5 ppm and carbon resonances at ca. 91.5 and 91 ppm).
However, both the 1H and 13C NMR spectra also show
duplicated sets of signals. This points to diastereomeric
mixtures in a nearly equal ratio as a result of the existence
of two chiral centers (C-2 and C-4). Likewise, imines 31–33
exhibit IR absorptions at around 1640 cm–1 along with
NMR shifts at around 8.5 and 156 ppm, characteristic of
the imino functional group. In addition, the unequivocal
solid-state structure of 31 was elucidated by single-crystal
X-ray analysis (Figure 4).[8]
Acetylation of 2-Aryl-4,4-bis(hydroxymethyl)oxazolidines
Oxazolidines 40 are in principle good candidates to pre-
pare the corresponding N-acetyloxazolidines because they
Figure 4. ORTEP diagram for compound 31.
Oxazolidines 29 and 30 equilibrate in solution with the already contain the heterocyclic unit. Thus, one would have
corresponding imines 34 and 35 (about 57% 29 and ca. expected the easy formation of such substances by conven-
50% 30), as oxazolidines 36 and 37 do with 31 and 32, tional treatment with acetic anhydride in pyridine. However,
respectively (about 57% 36 and ca. 17% 37; Table 3). In the this protocol failed to give the desired compounds 41, yield-
particular case of compound 30, we were able to isolate ing only the per-O-acetylated imines 42 instead (Scheme 4).
Scheme 3.
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Regiospecific Ring-Opening of 1,3-Oxazolidines
Scheme 4.
Accordingly, starting from the parent oxazolidines 8–14 54 (canonical form 19) by ring-opening. The third alterna-
the corresponding imines 43–49 were isolated with yields tive involves attack on the endocyclic oxygen atom plus
approaching 70%. Their structures were again corroborated ring-opening (canonical form 18) leading to per-O-acetyl-
by analytical and spectroscopic data. FTIR spectra showed imine 56.
stretching bands at ca. 1650 cm–1 (C=N bond) and NMR
Further studies were undertaken to shed light on the
resonances at ca. 8.4 and ca. 159 ppm, proving the existence
of an imino group. The solid state of 43 was also established
by single-crystal X-ray analysis (Figure 5).[8] Structures at-
tributed to 44–49 were also correlated with that found for
43.
mechanism of this acetylation. To this end, the reactions of
8–16 with hexadeuteriated acetic anhydride, (CD3CO)2O, in
pentadeuteriated pyridine, C5D5N, were monitored in an
NMR tube. The evolution of the NMR spectra over time
is depicted in Figure 6 (see also Figures S4 and S5 in the
Supporting Information).
For compound 8 the rapid formation of its mono- (57
and 58) and di-O-acetyl (59) derivatives can be observed.
This transformation occurs rapidly and, within 15 min, the
prevalent compound is essentially the di-O-acetylated ox-
azolidine 59, which disappears slowly to give exclusively 43
after 24 h (Scheme 6).
This rationale is also supported by the preparation of 59
by acetylation of 8. The process was quenched after 15 min
and 59 was isolated in 62% yield. The structure of this ox-
azolidine was confirmed again by FTIR (absorption of the
NH group at 3287 cm–1, absence of bands in the range be-
tween 1740 and 1606 cm–1) and NMR spectroscopic data
(signal at 5.60 ppm for 2-H and a carbon resonance at
91.08 ppm for C-2). The large coupling constant JNH,2-H
that 59 exhibits in [D6]DMSO suggests an axial disposition
of the NH group, in a similar way to compounds 8–16.
When 59 was subjected to the same acetylation conditions,
its complete transformation into 43 was observed. Similar
results were obtained in the acetylation of compounds 9–
16.
Figure 5. ORTEP diagram for per-O-acetyl imine 43.
The fate of this transformation is most likely influenced
by the anomeric effect present in oxazolidines 8–16. The
Acetylation Mechanism
Three possible pathways can be envisaged (Scheme 5). important contribution of canonical form 18 (Figure 3) ac-
Attack of the acetylating species on the nitrogen atom of counts for the observed reactivity as the most nucleophilic
the starting oxazolidine 50 would yield tetrahedral interme- center should be the oxygen atom of the ring and not the
diate 51, which could either evolve into N-acetyloxazolidine nitrogen. The nucleophilic site would attack acetic anhy-
52 (canonical form 17, Figure 3) after deprotonation or into dride and/or pyridinium acetate (60Ǟ61), thus enabling
Scheme 5.
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R. F. Martínez et al.
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Figure 6. Evolution with time of the NMR spectra of compound 8 after acetylation (* denotes pyridine signals).
Scheme 6. Reagents: i) (CD3CO)2O, C5D5N.
Scheme 7. Proposed mechanism for the acetylation of oxazolidines.
ring-opening to produce an iminium ion (62), which could terized. DFT calculations predict such an anomeric effect,
subsequently be deprotonated leading to an imine (43; in excellent agreement with X-ray crystal data. This stereo-
Scheme 7).
electronic effect directs the conformational bias of the het-
erocyclic ring and facilitates its regiospecific ring-opening
under acetylating conditions to give per-O-acetyl imines.
Oxazolidine–imine equilibria have been evaluated not only
Conclusions
Oxazolidines derived from TRIS that exhibit a strong for TRIS derivatives but also for 2-amino-2-methylpropane-
endo anomeric effect have been described and fully charac- 1,3-diol, 2-amino-2-methylpropan-1-ol, and 3-aminoprop-
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Regiospecific Ring-Opening of 1,3-Oxazolidines
1 H, OH), 4.80 (t, J = 5.6 Hz, 1 H, OH), 3.73 (d, J = 8.0 Hz, 1 H,
CH2 ring), 3.70 (d, J = 8.0 Hz, 1 H, CH2 ring), 3.45 (d, JCH2,OH
ane-1,2-diol. The results show that the amount of oxazolid-
ine increases as the number of potential hydroxy groups
capable of participating in the cyclization step increases.
=
5.6 Hz, 2 H, CH2), 3.44 (dd, JCH2,OH = 6.0, JH,H = 11.2 Hz, 1 H,
CH2), 3.36 (dd, JCH2,OH = 6.0, JH,H = 11.2 Hz, 1 H, CH2), 2.90 (d,
JNH,2-H = 10.8 Hz, 1 H, NH) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 145.6, 129.2 (q, JC-F = 31.5 Hz), 127.5, 127.4 (q,
JC-F = 269.8 Hz), 125.5 (q, JC-F = 3.7 Hz, C arom.), 91.1 (C-2),
69.6 (C-5), 67.9 (C-4), 63.4, 62.9 (2 C, CH2) ppm. C12H14F3NO3
(277.09): calcd. C 51.99, H 5.09, N 5.05; found C 51.67, H 4.98, N
5.04.
Experimental Section
General Methods: Melting points were determined with Gallen-
kamp and Electrothermal apparatuses. IR spectra were recorded in
the range of 4000–600 cm–1 with a FTIR THERMO spectropho-
tometer. Solid samples were recorded as KBr (Merck) pellets.
NMR spectra were recorded with a Bruker 400 AC/PC instrument
in different solvent systems. Assignments were confirmed by homo-
and hetero-nuclear double-resonance and DEPT (distortionless en-
hancement by polarization transfer). TMS was used as the internal
standard (δ = 0.00 ppm) and all J values are given in Hz. Micro-
analyses were determined with a Leco 932 analyzer. High-resolu-
tion mass spectra (chemical ionization) were recorded with an Au-
tospec-Q spectrometer by the Servicio de Espectrometría de Masas
de la Universidad de Sevilla (Spain).
4,4-Bis(hydroxymethyl)-2-(4-methoxycarbonylphenyl)oxazolidine (11):
Yield 3.70 g, 84%; m.p. 128–129 °C. IR (KBr): ν
= 3500–3100
˜
max
(OH), 1703 (C=O), 1612, 1576, 1513 (arom.) cm–1. 1H NMR
(400 MHz, [D6]DMSO): δ = 7.96 (d, J = 8.4 Hz, 2 H, H arom.),
7.56 (d, J = 8.4 Hz, 2 H, H arom.), 5.45 (d, J2-H,NH = 10.0 Hz, 1
H, 2-H), 4.85 (t, J = 5.6 Hz, 1 H, OH), 4.79 (t, J = 5.6 Hz, 1 H,
OH), 3.85 (s, 3 H, OCH3), 3.72 (d, J = 8.0 Hz, 1 H, CH2 ring),
3.68 (d, J = 8.0 Hz, 1 H, CH2 ring), 3.44 (d, JCH2,OH = 5.6 Hz, 2
H, CH2), 3.44 (dd, JCH2,OH = 5.6, JH,H = 10.8 Hz, 1 H, CH2), 3.37
(dd, JCH2,OH = 5.6, JH,H = 10.8 Hz, 1 H, CH2), 2.86 (d, JNH,2-H
=
General Procedure for the Synthesis of 2-Aryl-4,4-bis(hydroxymeth-
10.4 Hz, 1 H, NH) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
166.5 (C=O), 146.1, 129.9, 129.6, 127.1 (C arom.), 91.4 (C-2), 69.5
(C-5), 67.9 (C-4), 63.4, 62.8 (2 C, CH2), 52.6 (CH3) ppm.
C13H17NO5 (267.28): calcd. C 58.42, H 6.41, N 5.24; found C
58.28, H 6.47, N 5.47.
yl)oxazolidines:
(16.5 mmol) in a small volume of methanol was slowly added
to solution of α,α,α-tris(hydroxymethyl)methylamine (2.0 g,
A solution of the corresponding aldehyde
a
16.5 mmol) in water (16 mL). The mixture was stirred at room tem-
perature to produce a precipitate within a few minutes. When the
mixture did not precipitate spontaneously, it was evaporated in
vacuo to give a solid on standing or on cooling. The resulting prod-
uct was collected by filtration, washed successively with cold water,
ethanol, and diethyl ether, and recrystallized from ethanol or meth-
anol.
4,4-Bis(hydroxymethyl)-2-(3-nitrophenyl)oxazolidine (12): Yield
2.64 g, 63%; m.p. 92–93 °C. IR (KBr): ν
= 3300–3100 (OH),
˜
max
1618, 1586 (arom.), 1529, 1350 (NO2) cm–1. H NMR (400 MHz,
[D6]DMSO): δ = 8.26 (s, 1 H, H arom.), 8.20 (d, J = 7.6 Hz, 1 H,
H arom.), 7.88 (d, J = 7.6 Hz, 1 H, H arom.), 7.68 (t, J = 8.0 Hz,
1 H, H arom.), 5.56 (d, J2-H,NH = 10.8 Hz, 1 H, 2-H), 4.82 (t, J =
5.6 Hz, 1 H, OH), 4.80 (t, J = 5.6 Hz, 1 H, OH), 3.75 (d, J =
8.0 Hz, 1 H, CH2 ring), 3.70 (d, J = 7.6 Hz, 1 H, CH2 ring), 3.46
1
4,4-Bis(hydroxymethyl)-2-(4-nitrophenyl)oxazolidine
(8):
Yield
2.85 g, 68%; m.p. 108–109 °C. IR (KBr): ν = 3500–3100 (OH),
˜
max
1604, 1515 (arom.) cm–1. 1H NMR (400 MHz, [D6]DMSO): δ =
8.23 (d, J = 8.4 Hz, 2 H, H arom.), 7.70 (d, J = 8.4 Hz, 2 H, H
arom.), 5.55 (d, J2-H,NH = 10.8 Hz, 1 H, 2-H), 4.81 (t, J = 5.6 Hz,
2 H, OH), 3.74 (d, J = 7.6 Hz, 1 H, CH2 ring), 3.70 (d, J = 7.6 Hz,
1 H, CH2 ring), 3.46 (d, JCH2,OH = 5.6 Hz, 2 H, CH2), 3.42 (dd,
JCH2,OH = 5.6, JH,H = 11.2 Hz, 1 H, CH2), 3.32 (dd, JCH2,OH = 5.8,
JH,H = 11.2 Hz, 1 H, CH2), 2.99 (d, JNH,2-H = 10.8 Hz, 1 H,
NH) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 148.5, 147.8,
128.1, 123.9 (C arom.), 90.9 (C-2), 69.7 (C-5), 67.9 (C-4), 63.2, 62.9
(2 C, CH2) ppm. C11H14N2O5 (254.24): calcd. C 51.97, H 5.55, N
11.02; found C 51.67, H 5.72, N 11.10.
(d, JCH2,OH = 5.6 Hz, 2 H, CH2), 3.43 (dd, JCH2,OH = 5.6, JH,H
=
10.8 Hz, 1 H, CH2), 3.33 (dd, JCH2,OH = 5.6, JH,H = 10.8 Hz, 1
H, CH2), 3.02 (d, JNH,2-H = 10.8 Hz, 1 H, NH) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 148.1, 143.5, 133.6, 130.3, 123.5, 121.4
(C arom.), 90.7 (C-2), 69.7 (C-5), 67.9 (C-4), 63.3, 63.1 (2 C,
CH2) ppm. C11H14N2O5 (254.24): calcd. C 51.97, H 5.55, N 11.02;
found C 51.91, H 5.50, N 11.16.
4,4-Bis(hydroxymethyl)-2-(3-cyanophenyl)oxazolidine (13): Yield
2.51 g, 65%; m.p. 129–130 °C. IR (KBr): ν
= 3300–3100 (OH),
˜
max
2227 (CϵN), 1618, 1451 (arom.) cm–1. H NMR (400 MHz, [D6]-
DMSO): δ = 7.85 (s, 1 H, H arom.), 7.81 (d, J = 7.6 Hz, 1 H, H
arom.), 7.77 (d, J = 7.6 Hz, 1 H, H arom.), 7.60 (t, J = 7.6 Hz, 1
H, H arom.), 5.46 (d, J2-H,NH = 10.4 Hz, 1 H, 2-H), 4.80 (t, J =
6.0 Hz, 1 H, OH), 4.78 (t, J = 5.6 Hz, 1 H, OH), 3.72 (d, J =
8.0 Hz, 1 H, CH2 ring), 3.67 (d, J = 8.0 Hz, 1 H, CH2 ring), 3.44
1
4,4-Bis(hydroxymethyl)-2-(4-cyanophenyl)oxazolidine (9): Yield
2.13 g, 55%; m.p. 120–121 °C. IR (KBr): ν
= 3400–3200 (OH),
˜
max
1
2225 (CϵN), 1610, 1482, 1467 (arom.) cm–1. H NMR (400 MHz,
[D6]DMSO): δ = 7.84 (d, J = 8.0 Hz, 2 H, H arom.), 7.62 (d, J =
8.0 Hz, 2 H, H arom.), 5.49 (d, J2-H,NH = 10.8 Hz, 1 H, 2-H), 4.81
(t, J = 6.0 Hz, 1 H, OH), 4.79 (t, J = 6.0 Hz, 1 H, OH), 3.71 (d, J
= 7.6 Hz, 1 H, CH2 ring), 3.68 (d, J = 7.6 Hz, 1 H, CH2 ring), 3.44
(d, JCH2,OH = 6.0 Hz, 2 H, CH2), 3.43 (dd, JCH2,OH = 5.6, JH,H
=
11.4 Hz, 1 H, CH2), 3.35 (dd, JCH2,OH = 5.6, JH,H = 10.8 Hz, 1
H, CH2), 2.94 (d, JNH,2-H = 10.8 Hz, 1 H, NH) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 142.8 (CϵN), 132.5, 131.8, 130.4,
130.0, 119.2, 111.7 (C arom.), 90.9 (C-2), 69.7 (C-5), 67.8 (C-4),
63.3, 63.0 (2 C, CH2) ppm. C12H14N2O3 (234.25): calcd. C 61.53,
H 6.02, N 11.96; found C 61.50, H 6.05, N 12.15.
(d, JCH2,OH = 5.6 Hz, 2 H, CH2), 3.42 (dd, JCH2,OH = 5.6, JH,H
=
11.2 Hz, 1 H, CH2), 3.33 (dd, JCH2,OH = 5.6, JH,H = 11.2 Hz, 1
H, CH2), 2.93 (d, JNH,2-H = 10.8 Hz, 1 H, NH) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 146.5 (CϵN), 132.7, 127.8, 119.2,
111.4 (C arom.), 91.1 (C-2), 69.7 (C-5), 67.9 (C-4), 63.3, 62.9 (2 C,
CH2) ppm. C12H14N2O3 (234.25): calcd. C 61.53, H 6.02, N 11.96;
found C 61.42, H 6.24, N 11.86.
4,4-Bis(hydroxymethyl)-2-(3-methoxycarbonylphenyl)oxazolidine (14):
Yield 3.44 g, 78%; m.p. 119–120 °C. IR (KBr): ν
= 3400–3000
˜
max
1
4,4-Bis(hydroxymethyl)-2-(4-trifluoromethylphenyl)oxazolidine (10):
(OH), 1719 (C=O), 1604, 1515 (arom.) cm–1. H NMR (400 MHz,
[D6]DMSO): δ = 8.05 (s, 1 H, H arom.), 7.92 (d, J = 7.6 Hz, 1 H,
H arom.), 7.70 (d, J = 7.6 Hz, 1 H, H arom.), 7.53 (t, J = 7.6 Hz
1 H, H arom.), 5.45 (d, J2-H,NH = 10.8 Hz, 1 H, 2-H), 4.85 (t, J =
5.6 Hz, 1 H, OH), 4.79 (t, J = 5.6 Hz, 1 H, OH), 3.87 (s, 3 H,
Yield 3.02 g, 66%; m.p. 98–99 °C. IR (KBr): ν
= 3300–3100
˜
max
(OH), 1623, 1450 (arom.) cm–1. H NMR (400 MHz, [D6]DMSO):
δ = 7.40 (d, J = 8.0 Hz, 2 H, H arom.), 7.66 (d, J = 8.0 Hz, 2 H,
H arom.), 5.49 (d, J2-H,NH = 10.8 Hz, 1 H, 2-H), 4.84 (t, J = 5.6 Hz,
1
Eur. J. Org. Chem. 2010, 5263–5273
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5269

R. F. Martínez et al.
FULL PAPER
OCH3), 3.72 (d, J = 8.0 Hz, 1 H, CH2 ring), 3.68 (d, J = 8.0 Hz, 1
H, CH2 ring), 3.44 (d, JCH2,OH = 5.6 Hz, 2 H, CH2), 3.44 (dd,
1,3-diol, and prepared following the same procedure as used for
the synthesis of 11, compound 30 was isolated (3.44 g, 83%) as a
JCH2,OH = 5.6, JH,H = 10.8 Hz, 1 H, CH2), 3.37 (dd, JCH2,OH = 5.6, mixture of diastereomers 30a and 30b (1:2.3). Recrystallization of
JH,H = 10.8 Hz, 1 H, CH2), 2.85 (d, JNH,2-H = 11.2 Hz, 1 H, this mixture in ethanol gave rise to compound 30b; yield 2.07 g,
NH) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 166.6 (C=O), 50%; m.p. 106–107 °C. IR (KBr): ν
141.6, 131.7, 130.1, 129.4, 129.2, 127.3 (C arom.), 91.3 (C-2), 69.5
(C-5), 67.9 (C-4), 63.5, 62.9 (2 C, CH2), 52.7 (CH3) ppm. DMSO): δ = 7.94 (d, J = 8.0 Hz, 2 H, H arom.), 7.58 (d, J =
= 3300–3100 (OH), 1724
˜
max
1
(C=O), 1613, 1572, 1511 (arom.) cm–1. H NMR (400 MHz, [D6]-
C13H17NO5 (267.28): calcd. C 58.42, H 6.41, N 5.24; found C
58.45, H 6.40, N 5.31.
8.0 Hz, 2 H, H arom.), 5.49 (d, J2-H,NH = 12.0 Hz, 1 H, 2-H), 4.85
(t, J = 5.6 Hz, 1 H, OH), 3.85 (s, 3 H, OCH3), 3.79 (d, J = 7.6 Hz,
1 H, CH2 ring), 3.41 (d, J = 7.6 Hz, 1 H, CH2 ring), 3.40 (dd,
JCH2,OH = 6.0, JH,H = 10.1 Hz, 1 H, CH2), 3.32 (dd, JCH2,OH = 5.2,
JH,H = 10.4 Hz, 1 H, CH2), 2.95 (d, JNH,2-H = 10.4 Hz, 1 H, NH),
1.12 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
166.5 (C=O), 146.5, 129.6, 129.4, 127.2 (C arom.), 91.6 (C-2), 73.4
(C-5), 66.2 (CH2), 63.9 (C-4), 52.6 (OCH3), 22.7 (CH3) ppm.
C13H17NO4 (251.28): calcd. C 62.14, H 6.82, N 5.57; found C
62.08, H 6.71, N 5.80.
4,4-Bis(hydroxymethyl)-2-(4-methyl-3-nitrophenyl)oxazolidine (15):
Yield 2.57 g, 58%; m.p. 82–83 °C. IR (KBr): ν
= 3500–2500
˜
max
(OH, NH), 1621, 1565, 1495 (arom.), 1527, 1340 (NO2) cm–1. 1H
NMR (400 MHz, [D6]DMSO): δ = 8.01 (s, 1 H, H arom.), 7.67
(dd, J = 1.2, J = 7.9 Hz, 1 H, H arom.), 7.50 (d, J = 7.9 Hz, 1 H,
H arom.), 5.48 (d, J2-H,NH = 10.6 Hz, 1 H, 2-H), 4.79 (m, 2 H, 2
OH), 3.72 (d, J = 7.9 Hz, 1 H, CH2 ring), 3.67 (d, J = 7.9 Hz, 1
H, CH2 ring), 3.45 (d, JCH2,OH = 4.8 Hz, 2 H, CH2), 3.43 (dd,
JCH2,OH = 5.0, JH,H = 13.2 Hz, 1 H, CH2), 3.34 (dd, JCH2,OH = 5.7,
JH,H = 11.2 Hz, 1 H, CH2), 2.94 (d, JNH,2-H = 10.8 Hz, 1 H, NH),
2.52 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
149.1, 140.8, 133.2, 133.0, 131.7, 122.5 (C arom.), 90.6 (C-2), 69.7
(C-5), 67.8 (C-4), 63.63, 63.0 (2 C, CH2), 19.8 (CH3) ppm.
C12H16N2O5 (268.27): calcd. C 53.73, H 6.01, N 10.44; found C
53.68, H 6.17, N 10.55.
2-Methyl-2-(3-nitrobenzylideneamino)propane-1,3-diol (31): From 2-
amino-2-methylpropane-1,3-diol, compound 31 was obtained fol-
lowing the same procedure as used for the synthesis of 12; yield
3.54 g, 90%; m.p. 116–117 °C. IR (KBr): νmax = 1639 (C=N), 1534,
˜
1
1349 (NO2) cm–1. H NMR (400 MHz, [D6]DMSO): δ = 8.59 (s, 1
H, H arom.), 8.48 (s, 1 H, CH=N), 8.26 (d, J = 7.6 Hz, 1 H, H
arom.), 8.18 (d, J = 7.6 Hz, 1 H, H arom.), 7.72 (t, J = 7.8 Hz, 1
H, H arom.), 4.62 (t, J = 5.2 Hz, 2 H, 2 OH), 3.53 (dd, J = 5.6, J
= 10.0 Hz, 2 H, CH2), 3.46 (dd, J = 6.2, J = 10.2 Hz, 2 H, CH2),
1.18 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
156.8 (C=N), 148.5, 139.0, 134.8, 130.6, 125.0, 122.1 (C arom.),
66.2 (CH2), 65.9 (C-N), 18.7 (CH3) ppm. C11H14N2O4 (238.24):
calcd. C 55.46, H 5.92, N 11.76; found C 55.23, H 5.88, N 11.91.
4,4-Bis(hydroxymethyl)-2-(2-methoxy-4-nitrophenyl)oxazolidine (16):
Yield 3.47 g, 74%; m.p. 121–122 °C. IR (KBr): ν
= 3400–3200
˜
max
(OH), 1618, 1488 (arom.), 1521, 1360 (NO2) cm–1. 1H NMR
(400 MHz, [D6]DMSO): δ = 7.85 (d, J = 8.4 Hz, 1 H, H arom.),
7.72 (m, 2 H, H arom.), 5.56 (d, J2-H,NH = 9.6 Hz, 1 H, 2-H), 4.84
(t, J = 4.8 Hz, 1 H, OH), 4.78 (t, J = 4.6 Hz, 1 H, OH), 3.92 (s, 3
H, CH3), 3.76 (d, J = 7.8 Hz, 1 H, CH2 ring), 3.68 (d, J = 7.8 Hz,
1 H, CH2 ring), 3.46 (m, 4 H, 2 CH2), 2.86 (d, JNH,2-H = 9.6 Hz, 1
H, NH) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 157.8, 148.8,
136.2, 128.2, 115.9, 106.1 (C arom.), 86.4 (C-2), 69.4 (C-5), 67.7
(C-4), 63.2, 62.9 (2 C, CH2), 56.6 (CH3) ppm. C12H16N2O6
(284.27): calcd. C 50.70, H 5.67, N 9.85; found C 50.60, H 5.68, N
9.85.
2-Methyl-2-(3-nitrobenzylideneamino)propan-1-ol (32): From 2-
amino-2-methylpropan-1-ol, compound 32 was obtained following
the same procedure as used for the synthesis of 12; yield 3.63 g,
99%; m.p. 127–128 °C. IR (KBr): ν
= 3300 (OH), 1641 (C=N),
˜
max
1532, 1351 (NO2) cm–1. 1H NMR (400 MHz, [D6]DMSO): δ = 8.58
(s, 1 H, H arom.), 8.45 (s, 1 H, CH=N), 8.25 (dd, J = 7.6, J =
7.8 Hz, 1 H, H arom.), 8.18 (d, J = 7.6 Hz, 1 H, H arom.), 7.72 (t,
J = 7.8 Hz, 1 H, H arom.), 4.71 (t, J = 5.8 Hz, 1 H, OH), 3.39 (dd,
J = 5.6 Hz, 2 H, CH2), 1.20 (s, 6 H, CH3) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 155.6 (C=N), 148.5, 138.9, 134.7,
130.7, 125.1, 122.1 (C arom.), 69.8 (CH2), 62.1 (C-N), 24.4
(CH3) ppm. C11H14N2O3 (222.24): calcd. C 59.45, H 6.35, N 12.60;
found C 59.09, H 6.32, N 12.59.
4-Hydroxymethyl-4-methyl-2-(4-nitrophenyl)oxazolidine (29): From
2-amino-2-methylpropane-1,3-diol, and prepared following the
same procedure as used for the synthesis of 8, compound 29 was
isolated (2.71 g, 69%) as a mixture of diastereomers 29a and 29b
(1:1). IR (KBr): ν
= 3300–3100 (OH), 1519, 1346 (NO2), 1605,
˜
max
1482, 1450 (arom.) cm–1. C11H14N2O4 (238.24): calcd. C 55.46, H
1
5.92, N 11.76; found C 55.63, H 5.94, N 11.92. Data for 29a: H
3-(4-Nitrobenzylideneamino)propane-1,2-diol (33): From 3-amino-
propane-1,2-diol, compound 33 was obtained following the same
procedure as used for the synthesis of 8; yield 3.26 g, 88%; m.p.
NMR (400 MHz, [D6]DMSO): δ = 8.21 (d, J = 8.8 Hz, 2 H, H
arom.), 7.70 (d, J = 8.8 Hz, 2 H, H arom.), 5.57 (d, J2-H,NH
=
11.2 Hz, 1 H, 2-H), 4.98 (t, J = 5.6 Hz, 1 H, OH), 3.80 (d, J =
7.6 Hz, 1 H, CH2 ring), 3.42 (d, J = 7.6 Hz, 1 H, CH2 ring), 3.27
(d, J = 5.2 Hz, 2 H, CH2), 3.03 (d, JNH,2-H = 11.2 Hz, 1 H, NH),
1.15 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
149.0, 147.7, 128.1, 123.8 (C arom.), 91.1 (C-2), 73.4 (C-5), 65.6
(CH2), 63.8 (C-4), 22.7 (CH3) ppm. Data for 29b: 1H NMR
(400 MHz, [D6]DMSO): δ = 8.21 (d, J = 8.8 Hz, 2 H, H arom.),
7.70 (d, J = 8.8 Hz, 2 H, H arom.), 5.57 (d, J2-H,NH = 9.6 Hz, 1 H,
2-H), 4.94 (t, J = 5.6 Hz, 1 H, OH), 3.80 (d, J = 7.6 Hz, 1 H, CH2
ring), 3.42 (d, J = 7.6 Hz, 1 H, CH2 ring), 3.40 (dd, JCH2,OH = 5.6,
94–95 °C. IR (KBr): ν
= 3400–3100 (OH), 1643 (C=N), 1523,
˜
max
1343 (NO2) cm–1. H NMR (400 MHz, [D6]DMSO): δ = 8.45 (s, 1
H, CH=N), 8.29 (d, J = 8.8 Hz, 2 H, H arom.), 8.00 (d, J = 8.8 Hz,
2 H, H arom.), 4.72 (d, J = 5.2 Hz, 1 H, OH), 4.64 (t, J = 5.6 Hz,
1 H, OH), 3.85 (ddd, J = 11.6, J = 4.2, J = 1.3 Hz, 1 H, CH2N),
3.78 (m, 1 H, CHOH), 3.50 (dd, J = 12.0, J = 6.8 Hz, 1 H, CH2N),
3.43 (d, J = 5.6 Hz, 2 H, CH2OH) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 160.8 (C=N), 148.9, 142.3, 129.3, 124.3 (C arom.),
71.5 (CH), 64.7, 64.6 (2 C, 2 CH2) ppm. C10H12N2O4 (224.21):
calcd. C 53.57, H 5.39, N 12.49; found C 53.25, H 5.29, N 12.26.
1
JH,H = 10.8 Hz, 1 H, CH2), 3.32 (dd, JCH2,OH = 5.6, JH,H
=
Oxazolidine–Imine Equilibria: Oxazolidines 8–16, 29 and 30 and
imines 31–33 form equilibria in DMSO solution with the corre-
sponding imines 20–28, 34, and 35, oxazolidines 36–38, and oxaz-
ine 39.
10.8 Hz, 1 H, CH2), 3.12 (d, JNH,2-H = 10.4 Hz, 1 H, NH), 1.08 (s, 3
H, CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 148.6, 147.6,
128.0, 123.7 (C arom.), 90.5 (C-2), 73.4 (C-5), 66.0 (CH2), 63.8 (C-
4), 22.2 (CH3) ppm.
1
(2R,4S)- and (2S,4R)-4-Hydroxymethyl-4-methyl-2-(4-methoxy- Spectroscopic Data for 20: H NMR (400 MHz, [D6]DMSO): δ =
carbonylphenyl)oxazolidine (30b): From 2-amino-2-methylpropane-
8.55 (s, 1 H, CH=N), 8.29 (d, J = 8.8 Hz, 2 H, H arom.), 8.04 (d,
5270
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5263–5273

Regiospecific Ring-Opening of 1,3-Oxazolidines
J = 8.8 Hz, 2 H, H arom.), 4.52 (t, J = 5.6 Hz, 3 H, OH), 3.62 (d, J = 10.6 Hz, 2 H, CH2), 3.45 (dd, J = 6.0, J = 10.8 Hz, 2 H, CH2),
J = 5.6 Hz, 6 H, CH2) ppm. 13C NMR (100 MHz, [D6]DMSO): δ
= 157.7 (C=N), 148.2, 142.5, 128.8, 123.7 (C arom.), 68.4 (C-N),
61.6 (3 C, CH2) ppm.
1.17 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
157.1 (C=N), 148.8, 142.9, 129.3, 124.2 (C arom.), 66.2 (C-N), 66.1
(CH2), 18.7 (CH3) ppm.
1
Spectroscopic Data for 21: H NMR (400 MHz, [D6]DMSO): δ =
Compound 30b equilibrated in DMSO solution with its dia-
8.50 (s, 1 H, CH=N), 7.96 (d, J = 8.0 Hz, 2 H, H arom.), 7.89 (d, stereoisomer 30a and imine 35.
J = 8.0 Hz, 2 H, H arom.), 4.88 (t, J = 5.6 Hz, 3 H, OH), 3.61 (d,
Spectroscopic Data for 30a: 1H NMR (400 MHz, [D6]DMSO): δ =
J = 5.6 Hz, 6 H, CH2) ppm. 13C NMR (100 MHz, [D6]DMSO): δ
= 158.2 (C=N), 140.9 (CϵN), 132.6, 128.6, 118.9, 112.4 (C arom.),
68.3 (C-N), 61.7 (3 C, CH2) ppm.
7.97 (d, J = 8.4 Hz, 2 H, H arom.), 7.58 (d, J = 8.4 Hz, 2 H, H
arom.), 5.50 (d, J2-H,NH = 11.6 Hz, 1 H, 2-H), 4.97 (t, J = 5.6 Hz,
1 H, OH), 3.86 (s, 3 H, OCH3), 3.79 (d, J = 7.2 Hz, 1 H, CH2
ring), 3.41 (d, J = 7.2 Hz, 1 H, CH2 ring), 3.30 (d, J = 4.8 Hz, 2
1
Spectroscopic Data for 22: H NMR (400 MHz, [D6]DMSO): δ =
8.51 (s, 1 H, CH=N), 7.99 (d, J = 8.0 Hz, 2 H, H arom.), 7.79 (d, H, CH2), 2.91 (d, JNH,2-H = 11.2 Hz, 1 H, NH), 1.14 (s, 3 H,
J = 8.0 Hz, 2 H, H arom.), 4.52 (t, J = 5.6 Hz, 3 H, OH), 3.63 (d, CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 166.5 (C=O),
J = 5.6 Hz, 6 H, CH2) ppm. 13C NMR (100 MHz, [D6]DMSO): δ
146.3, 129.6, 129.4, 127.0 (C arom.), 91.0 (C-2), 73.2 (C-5), 65.5
= 158.6 (C=N), 141.0, 130.6 (q, JC-F = 11.3 Hz), 128.9, 125.8 (q, (CH2), 63.9 (C-4), 52.6 (OCH3), 22.4 (CH3) ppm.
JC-F = 3.8 Hz, C arom.), 68.5 (C-N), 62.2 (CH2) ppm.
1
Spectroscopic Data for 35: H NMR (400 MHz, [D6]DMSO): δ =
1
Spectroscopic Data for 23: H NMR (400 MHz, [D6]DMSO): δ =
8.50 (s, 1 H, CH=N), 8.02 (d, J = 7.6 Hz, 2 H, H arom.), 7.91 (d, J = 8.4 Hz, 2 H, H arom.), 4.59 (t, J = 5.6 Hz, 2 H, OH), 3.87 (s,
J = 8.0 Hz, 2 H, H arom.), 4.50 (t, J = 5.6 Hz, 3 H, OH), 3.87 (s, 3 H, OCH3), 3.52 (dd, J = 10.8, J = 5.6 Hz, 2 H, CH2), 3.43 (dd,
3 H, OCH3), 3.62 (d, J = 5.6 Hz, 6 H, CH2) ppm. 13C NMR J = 10.8, J = 5.6 Hz, 2 H, CH2), 1.16 (s, 3 H, CH3) ppm. 13C NMR
8.42 (s, 1 H, CH=N), 8.02 (d, J = 8.4 Hz, 2 H, H arom.), 7.90 (d,
(100 MHz, [D6]DMSO): δ = 166.5 (C=O), 158.9 (C=N), 141.5,
131.2, 129.8, 128.5 (C arom.), 68.5 (C-N), 62.2 (3 C, CH2) ppm.
(100 MHz, [D6]DMSO): δ = 166.4 (C=O), 157.7 (C=N), 141.4,
131.2, 129.8, 128.5 (C arom.), 65.8 (CH2), 65.5 (C-N), 52.7 (OCH3),
18.8 (CH3) ppm.
1
Spectroscopic Data for 24: H NMR (400 MHz, [D6]DMSO): δ =
8.61 (s, 1 H, H arom.), 8.54 (s, 1 H, CH=N), 8.27 (dd, J = 2.4, J Spectroscopic Data for 36a: 1H NMR (400 MHz, [D6]DMSO): δ =
= 8.0 Hz, 1 H, H arom.), 7.87 (d, J = 7.6 Hz, 1 H, H arom.), 7.74 8.27 (m, 1 H, H arom.), 8.18 (m, 1 H, H arom.), 7.87 (d, J = 7.6 Hz,
(J = 8.0 Hz, 1 H, H arom.), 4.54 (t, J = 5.6 Hz, 3 H, OH), 3.62 (d, 1 H, H arom.), 7.66 (m, 1 H, H arom.), 5.59 (d, J2-H,NH = 10.8 Hz,
J = 5.6 Hz, 6 H, CH2) ppm. 13C NMR (100 MHz, [D6]DMSO): δ
= 157.9 (C=N), 148.6, 139.1, 134.9, 130.6, 125.1, 122.0 (C arom.),
68.6 (C-N), 62.2 (3 C, CH2) ppm.
1 H, 2-H), 4.94 (t, J = 5.6 Hz, 1 H, OH), 3.82 (d, J = 8.0 Hz, 1 H,
CH2 ring), 3.43 (m, 1 H, CH2 ring), 3.28 (d, J = 5.6 Hz, 2 H, CH2),
3.07 (d, JNH,2-H = 11.2 Hz, 1 H, NH), 1.17 (s, 3 H, CH3) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 148.1, 143.6, 133.5, 130.3,
123.5, 121.3 (C arom.), 90.3 (C-2), 73.4 (C-5), 65.6 (CH2), 63.9 (C-
4), 22.7 (CH3) ppm.
1
Spectroscopic Data for 25: H NMR (400 MHz, [D6]DMSO): δ =
8.45 (s, 1 H, CH=N), 8.26 (s, 1 H, H arom.), 8.08 (d, J = 8.0 Hz,
1 H, H arom.), 7.89 (d, J = 8.0 Hz, 1 H, H arom.), 7.65 (t, J =
8.0 Hz, 1 H, H arom.), 4.52 (t, J = 5.6 Hz, 3 H, OH), 3.59 (d, J =
5.6 Hz, 6 H, CH2) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
Spectroscopic Data for 36b: 1H NMR (400 MHz, [D6]DMSO): δ =
8.27 (m, 1 H, H arom.), 8.18 (m, 1 H, H arom.), 7.87 (d, J = 7.6 Hz,
157.9 (C=N), 138.5 (CϵN), 134.0, 132.9, 131.6, 130.2, 119.1, 112.1 1 H, H arom.), 7.66 (m, 1 H, H arom.), 5.59 (d, J2-H,NH = 10.8 Hz,
(C arom.), 68.4 (C-N), 62.1 (3 C, CH2) ppm.
1 H, 2-H), 4.89 (t, J = 5.6 Hz, 1 H, OH), 3.80 (d, J = 8.0 Hz, 1 H,
CH2 ring), 3.43 (m, 1 H, CH2 ring), 3.40 (dd, JCH2,OH = 5.6, JH,H
= 10.8 Hz, 1 H, CH2), 3.33 (dd, JCH2,OH = 5.6, JH,H = 10.8 Hz, 1
H, CH2), 3.18 (d, JNH,2-H = 10.4 Hz, 1 H, NH), 1.10 (s, 3 H,
CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 148.1, 143.8,
133.7, 130.2, 123.3, 121.5 (C arom.), 90.9 (C-2), 73.4 (C-5), 66.0
(CH2), 63.8 (C-4), 22.3 (CH3) ppm.
1
Spectroscopic Data for 26: H NMR (400 MHz, [D6]DMSO): δ =
8.50 (s, 1 H, CH=N), 8.37 (s, 1 H, H arom.), 8.01 (d, J = 7.6 Hz,
2 H, H arom.), 7.60 (t, J = 7.6 Hz, 1 H, H arom.), 4.49 (t, J =
5.6 Hz, 3 H, OH), 3.88 (s, 3 H, OCH3), 3.62 (d, J = 5.6 Hz, 6 H,
CH2) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 166.6 (C=O),
158.8 (C=N), 137.9, 133.3, 131.1, 130.3, 129.5, 128.4 (C arom.),
68.3 (C-N), 62.2 (3 C, CH2) ppm.
1
Spectroscopic Data for 37: H NMR (400 MHz, [D6]DMSO): δ =
8.27 (dd, J = 2.2, J = 8.1 Hz, 1 H, H arom.), 8.18 (d, J = 7.6 Hz,
1 H, H arom.), 7.88 (d, J = 7.6 Hz, 1 H, H arom.), 7.66 (t, J =
7.9 Hz, 1 H, H arom.), 5.60 (d, J2-H,NH = 11.2 Hz, 1 H, 2-H), 3.55
(d, J = 7.2 Hz, 1 H, CH2), 3.48 (d, J = 7.6 Hz, 1 H, CH2), 3.20 (d,
JNH,2-H = 11.2 Hz, 1 H, H arom.), 1.21 (s, 3 H, CH3), 1.15 (s, 3 H,
CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 148.0, 143.8,
133.7, 130.1, 123.3, 121.4 (C arom.), 90.7 (C-2), 77.4 (C-5), 59.9
(C-4), 26.3, 26.0 (2 C, CH3) ppm.
1
Spectroscopic Data for 27: H NMR (400 MHz, [D6]DMSO): δ =
8.45 (s, 1 H, CH=N), 8.36 (s, 1 H, H arom.), 7.98 (m, 1 H, H
arom.), 7.56 (d, J = 7.6 Hz, 1 H, H arom.), 4.50 (t, J = 5.4 Hz, 3
H, OH), 3.61 (d, J = 4.8 Hz, 6 H, CH2), 2.55 (s, 3 H, CH3) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 157.7 (C=N), 149.6, 136.9,
134.8, 133.5, 132.8, 123.3 (C arom.), 68.4 (C-N), 62.18 (3 C, CH2),
20.0 (CH3) ppm.
1
Spectroscopic Data for 28: H NMR (400 MHz, [D6]DMSO): δ =
Spectroscopic Data for 38: Diastereomeric ratio 1:2.1. 13C NMR
(100 MHz, [D6]DMSO): δ = 128.1, 128.0, 123.6, 123.5 (C arom.),
87.1, 86.8 (C-2), 72.5, 71.9 (CH2OH), 62.7, 62.6 (CH), 51.6, 49.9
(CH2N) ppm.
8.80 (s, 1 H, CH=N), 8.14 (d, J = 9.2 Hz, 1 H, H arom.), 7.85 (m,
2 H, H arom.), 7.72 (m, 1 H, H arom.), 4.51 (t, J = 5.6 Hz, 3 H,
OH), 3.62 (d, J = 5.2 Hz, 6 H, CH2), 2.09 (s, 3 H, OCH3) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 153.6 (C=N), 158.9, 149.9,
131.1, 127.9, 115.8, 107.2 (C arom.), 69.0 (C-N), 62.3 (3 C, CH2),
31.2 (OCH3) ppm.
Spectroscopic Data for 39: Diastereomeric ratio 1:1.3. 13C NMR
(100 MHz, [D6]DMSO): δ = 91.8, 91.3 (C-2), 77.9, 77.5 (CH2O),
63.5, 63.2 (CH), 49.1, 48.4 (CH2N) ppm.
1
Spectroscopic Data for 34: H NMR (400 MHz, [D6]DMSO): δ =
8.48 (s, 1 H, CH=N), 8.28 (d, J = 8.4 Hz, 2 H, H arom.), 8.03 (d, General Procedure for the Synthesis of Per-O-acetyl Imines Derived
J = 8.4 Hz, 2 H, H arom.), 4.62 (m, 3 H, 2 OH), 3.54 (dd, J = 5.4, from TRIS: Acetic anhydride (6.5 mL) was added to a solution of
Eur. J. Org. Chem. 2010, 5263–5273
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5271

R. F. Martínez et al.
FULL PAPER
the corresponding oxazolidine (5.0 mmol) in pyridine (6.7 mL).
The reaction mixture was kept at 0 °C for 24 h and then poured
into ice–water. When the resulting product was an oil, it was ex-
tracted with chloroform (3ϫ50 mL) and the organic layer was
washed sequentially with 1  HCl (2ϫ50 mL), a saturated solution
of NaHCO3 (2ϫ50 mL), and distilled water (2ϫ50 mL). The or-
ganic layer was dried (MgSO4) and the solvents evaporated. Solid
substances were collected by filtration, washed with distilled water,
and dried under vacuum.
1,3-Diacetoxy-2-acetoxymethyl-2-(3-cyanobenzylideneamino)-
propane (48): This compound was obtained from 13; yield 1.12 g,
62%; m.p. 94–96 °C. IR (KBr): ν
= 2227 (CϵN), 1742 (C=O),
˜
max
1645 (C=N), 1598, 1580, 1477 (arom.) cm–1. H NMR (400 MHz,
CDCl3): δ = 8.39 (s, 1 H, CH=N), 8.08 (s, 1 H, H arom.), 8.00 (dt,
J = 1.2, J = 1.2, J = 7.6 Hz, 1 H, H arom.), 7.76 (dt, J = 1.2, J =
1.2, J = 7.6 Hz, 1 H, H arom.), 7.58 (t, J = 7.6 Hz, 1 H, H arom.),
4.39 (s, 6 H, CH2), 2.09 (s, 9 H, OAc) ppm. 13C NMR (100 MHz,
CDCl3): δ = 170.5 (C=O), 158.6 (C=N), 137.0 (CϵN), 134.4, 132.4,
131.9, 129.6, 118.2, 113.2 (C arom.), 63.9 (C-N), 63.5 (CH2), 20.8
(3 C, CH3, OAc) ppm. C18H20N2O6 (360.36): calcd. C 59.99, H
5.59, N 7.77; found C 59.75, H 5.72, N 7.67.
1
1,3-Diacetoxy-2-acetoxymethyl-2-(4-nitrobenzylideneamino)propane
(43): This compound was obtained from 8; yield 1.33 g, 70%; m.p.
85–86 °C. IR (KBr): ν
= 1738 (C=O), 1649 (C=N), 1601, 1516,
˜
max
1471 (arom.) cm–1. H NMR (400 MHz, CDCl3): δ = 8.47 (s, 1 H,
CH=N), 8.29 (d, J = 8.8 Hz, 2 H, H arom.), 7.93 (d, J = 8.8 Hz,
2 H, H arom.), 4.40 (s, 6 H, CH2), 2.08 (s, 9 H, OAc) ppm. 13C
NMR (100 MHz, CDCl3): δ = 170.5 (C=O), 158.7 (C=N), 149.4,
141.2, 129.1, 123.9 (C arom.), 64.2 (C-N), 63.4 (CH2), 20.8 (3 C,
CH3, OAc) ppm. C17H20N2O8 (380.35): calcd. C 53.68, H 5.30, N
7.37; found C 53.77, H 5.39, N 7.58.
1
1,3-Diacetoxy-2-acetoxymethyl-2-(3-methoxycarbonylbenzylidene-
amino)propane (49): This compound was obtained from 14 as an
oil; yield 1.59 g, 81%). IR (NaCl): ν
= 1742 (C=O), 1649
˜
max
(C=N), 1604, 1587 (arom.) cm–1. 1H NMR (400 MHz, CDCl3): δ
= 8.42 (s, 1 H, CH=N), 8.37 (s, 1 H, H arom.), 8.13 (d, J = 7.6 Hz,
1 H, H arom.), 8.00 (d, J = 8.0 Hz, 1 H, H arom.), 7.52 (t, J =
7.6 Hz, 1 H, H arom.), 4.38 (s, 6 H, CH2), 3.95 (s, 3 H, OCH3),
2.07 (s, 9 H, OAc) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.6
(C=O), 166.6 (C=O), 159.8 (C=N), 136.4, 132.2, 131.1, 130.7,
129.9, 128.9 (C arom.), 63.6 (C-N), 63.6 (CH2), 52.4 (OCH3), 20.9
(3 C, CH3, OAc) ppm. HRMS (CI): calcd. for C19H23NO8 [M +
H]+ 394.1502; found 394.1504.
1,3-Diacetoxy-2-acetoxymethyl-2-(4-cyanobenzylideneamino)-
propane (44): This compound was obtained from 9; yield 1.30 g,
72%; m.p. 65–66 °C. IR (KBr): ν
= 2228 (CϵN), 1738 (C=O),
˜
max
1649 (C=N), 1601, 1472 (arom.) cm–1 1H NMR (400 MHz,
.
CDCl3): δ = 8.41 (s, 1 H, CH=N), 7.86 (d, J = 8.8 Hz, 2 H, H
arom.), 7.73 (d, J = 8.8 Hz, 2 H, H arom.), 4.38 (s, 6 H, CH2), 2.07
(s, 9 H, OAc) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.4 (C=O),
159.1 (C=N), 139.7 (CϵN), 132.5, 128.8, 118.4, 114.6 (C arom.),
64.1 (C-N), 63.4 (CH2), 20.8 (3 C, CH3, OAc) ppm. C18H20N2O6
(360.36): calcd. C 59.99, H 5.59, N 7.77; found C 60.00, H 5.59, N
7.82.
4,4-Bis(acetoxymethyl)-2-(4-nitrophenyl)oxazolidine (59): Acetic an-
hydride (6.5 mL) was added to a solution of oxazolidine 8
(5.0 mmol) in pyridine (6.7 mL). The reaction mixture was kept at
0 °C for 15 min and then it was poured into ice–water. The re-
sulting product was extracted with chloroform (3ϫ50 mL) and the
organic layer was washed sequentially with 1  HCl (2ϫ50 mL),
a saturated solution of NaHCO3 (2ϫ50 mL), and distilled water
(2ϫ50 mL). The organic layer was dried (MgSO4) and evaporated;
1,3-Diacetoxy-2-acetoxymethyl-2-(4-trifluorobenzylideneamino)-
propane (45): This compound was obtained from 10 as an oil; yield
1.41 g, 70%. IR (NaCl): ν
= 1745 (C=O), 1646 (C=N), 1544,
˜
yield 1.05 g, 62%; m.p. 69–70 °C. IR (KBr): ν
= 1738 (C=O),
max
˜
max
1466 (arom.), 1232 (C–O) cm–1. H NMR (400 MHz, CDCl3): δ =
8.41 (s, 1 H, CH=N), 7.87 (d, J = 8.0 Hz, 2 H, H arom.), 7.69 (d,
J = 8.4 Hz, 2 H, H arom.), 4.38 (s, 6 H, CH2), 2.06 (s, 9 H,
OAc) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.8, 170.9, 170.5
(C=O), 159.5 (C=N), 129.9, 128.6, 126.1, 125, 6 (C arom.), 63.5
(CH2), 60.2 (C-N), 20.8 (3 C, CH3, OAc) ppm. HRMS (CI): calcd.
C18H20F3NO6 [M + H]+ 404.1321; found 404.1321.
1
1606, 1520, 1465 (arom.), 1249 (C–O) cm–1. H NMR (400 MHz,
CDCl3): δ = 8.24 (d, J = 8.8 Hz, 2 H, H arom.), 7.67 (d, J = 8.8 Hz,
2 H, H arom.), 5.60 (s, 1 H, 2-H), 4.27 (d, J = 11.2 Hz, 1 H, CH2),
4.21 (d, J = 11.2 Hz, 1 H, CH2), 4.16 (d, J = 11.2 Hz, 1 H, CH2),
4.08 (d, J = 11.2 Hz, 1 H, CH2), 3.90 (d, J = 11.2 Hz, 1 H, CH2),
3.80 (d, J = 11.2 Hz, 1 H, CH2), 2.55 (s, 1 H, NH), 2.14, 2.07 (s, 6
1
1
H, OAc) ppm. H NMR (400 MHz, [D6]DMSO): δ = 8.24 (d, J =
8.8 Hz, 2 H, H arom.), 7.71 (d, J = 8.8 Hz, 2 H, H arom.), 5.63 (d,
J2-H,NH = 9.5 Hz, 1 H, 2-H), 4.16 (d, J = 11.2 Hz, 1 H, CH2), 4.09
(d, J = 11.2 Hz, 1 H, CH2), 4.01 (d, J = 11.2 Hz, 1 H, CH2), 3.97
(d, J = 11.2 Hz, 1 H, CH2), 3.78 (d, J = 11.2 Hz, 1 H, CH2), 3.70
(d, J = 11.2 Hz, 1 H, CH2), 3.68 (d, JNH,2-H = 9.5 Hz, 1 H, NH),
2.06, 1.99 (s, 6 H, OAc) ppm. 13C NMR (100 MHz, CDCl3): δ =
170.8, 170.7 (C=O), 148.2, 145.8, 127.2, 123.8 (C arom.), 91.1 (C-
2), 70.6 (C-5), 65.2, 64.9 (CH2), 64.4 (C-4), 20.9, 20.8 (3 C, CH3,
OAc) ppm. C15H18N2O7 (338.31): calcd. C 53.25, H 5.36, N 8.28;
found C 53.06, H 5.36, N 8.25.
1,3-Diacetoxy-2-acetoxymethyl-2-(4-methoxycarbonylbenzylidene-
amino)propane (46): This compound was obtained from 11; yield
1.20 g, 61%; m.p. 66–67 °C. IR (KBr): ν
= 1732, 1720 (C=O),
˜
max
1646 (C=N), 1602, 1471 (arom.) cm–1
.
1H NMR (400 MHz,
CDCl3): δ = 8.43 (s, 1 H, CH=N), 8.10 (d, J = 7.6 Hz, 2 H, H
arom.), 7.82 (d, J = 7.6 Hz, 2 H, H arom.), 4.39 (s, 6 H, CH2), 3.95
(s, 3 H, OCH3), 2.07 (s, 9 H, OAc) ppm. 13C NMR (100 MHz,
CDCl3): δ = 170.5 (C=O), 166.6 (C=O), 159.9 (C=N), 139.8, 132.4,
129.9, 128.3 (C arom.), 63.8 (C-N), 63.6 (CH2), 52.4 (OCH3), 20.8
(3 C, CH3, OAc) ppm. C19H23NO8 (393.39): calcd. C 58.01, H 5.89,
N 3.56; found C 57.95, H 5.83, N 3.47.
Supporting Information (see also the footnote on the first page of
this article): Tables S1 and S2, Figures S1–S5, 1H and 13C NMR
spectra, and computational data.
1,3-Diacetoxy-2-acetoxymethyl-2-(3-nitrobenzylideneamino)propane
(47): This compound was obtained from 12; yield 1.64 g, 86%; m.p.
74–76 °C. IR (KBr): ν
= 1748 (C=O), 1649 (C=N), 1612, 1469
˜
max
(arom.) cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.59 (t, J = 1.8 Hz,
1 H, H arom.), 8.46 (s, 1 H, CH=N), 8.31 (dd, J = 2.2, J = 8.2 Hz,
1 H, H arom.), 8.11 (d, J = 7.6 Hz, 1 H, H arom.), 7.64 (t, J =
7.8 Hz, 1 H, H arom.), 4.39 (s, 6 H, CH2), 2.08 (s, 9 H, OAc) ppm.
Acknowledgments
This work was supported by the Junta de Extremadura
13C NMR (100 MHz, CDCl3): δ = 170.5 (C=O), 158.4 (C=N), (PRI08A032), the Ministerio de Educación y Ciencia (MEC) and
148.6, 137.6, 133.8, 129.8, 125.7, 123.2 (C arom.), 63.7 (C-N), 63.5
(CH2), 20.8 (3 C, CH3, OAc) ppm. C17H20N2O8 (380.35): calcd. C (CTQ2007-66641). R. F. M. thanks the Junta de Extremadura for
53.68, H 5.30, N 7.37; found C 53.60, H 5.31, N 7.45. a fellowship.
Fondos Europeos para el Desarrollo Regional (FEDER)
5272
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5263–5273

Regiospecific Ring-Opening of 1,3-Oxazolidines
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Received: May 5, 2010
Published Online: August 5, 2010
Eur. J. Org. Chem. 2010, 5263–5273
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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