Schiff bases from TRIS and formylpyridines: Structure and mechanistic rationale aided by DFT calculations

Article abstract of DOI:10.1002/ejoc.201000922

This paper describes the synthesis and structural elucidation of 1,3-oxazolidines derived from tris(hydroxymethyl)aminomethane (TRIS) and pyridine-based aldehydes. Divergent results were obtained with other formylpyridines, such aspyridoxal, in which intr

Full text of DOI:10.1002/ejoc.201000922

FULL PAPER
DOI: 10.1002/ejoc.201000922
Schiff Bases from TRIS and Formylpyridines: Structure and Mechanistic
Rationale Aided by DFT Calculations
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]
Keywords: Regioselectivity / Acylation / Schiff bases / Density functional calculations / Heterocycles
This paper describes the synthesis and structural elucidation
of 1,3-oxazolidines derived from tris(hydroxymethyl)amino-
methane (TRIS) and pyridine-based aldehydes. Divergent
results were obtained with other formylpyridines, such as
pyridoxal, in which intramolecular hydrogen-bonding
largely stabilizes the iminic structure. The oxazolidines may
undergo ring-opening under acetylating conditions to afford
imines through different mechanistic pathways, which have
also been evaluated by DFT calculations.
Introduction
Tris(hydroxymethyl)aminomethane (TRIS, 1) is a versatile
precursor of substituted 1,3-oxazolidines.[1] The usual syn-
thetic strategy involves (Scheme 1, i–iv) the condensation of
1 with two moles of an aldehyde in benzene at reflux with
azeotropic removal of water, which affords 1-aza-3,7-dioxa-
bicyclo[3.3.0]octane derivatives 2.[1,2] Acetylation with ace-
tyl chloride followed by hydrolysis gives rise to the corre-
sponding oxazolidine hydrochloride 3. Neutralization with
base ultimately causes acetyl migration to produce the N-
acetyloxazolidine 4.[3] This tedious protocol can signifi-
cantly be abbreviated by an environmentally benign one-
step synthesis, introduced recently by our group, that in-
volves the direct condensation of 1 with aldehydes bearing
electron-withdrawing substituents in an aqueous medium
(Scheme 1, v).[4]
In an attempt to test the scope of this methodology in
the case of heterocyclic aldehydes, we herein report the con-
densation of TRIS with formylpyridines and provide a full
characterization by spectroscopic and crystallographic
methods. In addition, the mechanism of this acetylation
and ring closure has been interpreted with the aid of DFT
calculations at the B3LYP/6-31G* level of theory.
Scheme 1. Reagents and conditions: i) RCHO (2 mol), C6H6, ∆;
ii) CH3COCl; iii) H2O; iv) NaOH (aq.) or NaHCO3 (aq.);
v) XC6H4CHO, H2O.
Results and Discussion
Reaction of TRIS with Formyl Heterocycles
The condensation of 1 with formylpyridines, namely 4-
formylpyridine, 3-fluoro-4-formylpyridine, and 4-formyl-
pyridine N-oxide in aqueous medium did not produce the
expected imine derivatives, but the alternative oxazolidines
6–8 instead (in yields of 51–91%).
[a] Departamento de Química Orgánica e Inorgánica, QUOREX
Research Group, Facultad de Ciencias, Universidad de
Extremadura,
06071 Badajoz, Spain
Fax: +34-924-271-149
E-mail: rmarvaz@unex.es
[b] Department of Chemistry, University of Southampton,
Highfield, Southampton SO17 1BJ, United Kingdom
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000922.
View this journal online at
wileyonlinelibrary.com
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Schiff Bases from TRIS and Formylpyridines
Extension of the reaction to 3-formyl- and 4-formylquin-
oline yielded the oxazolidines 9 (87%) and 10 (56%),
respectively. Starting from a related amino alcohol, 2-
amino-2-methyl-1,3-propanediol, and 4-formylquinoline,
compound 11 was isolated in 27% yield.
Figure 2. Bond lengths [Å] for compound 6 involved in the anom-
eric effect as determined by (a) X-ray crystallography and (b) DFT
calculations.
Table 1. Second-order perturbational energies (E2) in 6 from NBO
The structures attributed to 6–11 are consistent with
their spectroscopic data and elemental analyses. Thus, their
IR spectra show typical stretching bands for OH and NH
bonds in the range 3500–3000 cm–1 and without any other
bands above 1617 cm–1, which could be attributed to the
C=N bond, thereby ruling out an iminic structure. The
presence of the oxazolidine ring is evidenced by NMR sig-
nals at around 5.5–6.0 ppm (2-H) and 85–90 ppm (C-2).
Moreover, the structure of compound 6 was unequivocally
established by single-crystal X-ray diffraction analysis (Fig-
ure 1 left).[5]
analysis.
[a]
Donor NBO
Acceptor NBO
E2 [kcalmol–1]
LPN
LPO1
LPO1
σ*C2–O1
σ*C2–N
σ*C2–N
8.34
1.57
5.86
[a] Determined at the B3LYP/6-31G* level of theory.
Oxazolidine 11 was also observed as a diastereomeric
mixture (ratio 11a/11b, 54:46) as a result of the existence of
two stereogenic centers.
When 2-formylquinoline was employed as the starting
material, the expected oxazolidine 13 was not detected. In-
stead a substance identified as dimer 14 was isolated in 10%
yield as a single diastereomer, for which crystals suitable for
Figure 1. Crystal structure of 6 showing the conformation of the
heterocyclic ring (left) and calculated geometry of 6 (right).
The geometry of 6 in the gas phase (Figure 1 right), com- X-ray analysis could not be obtained.
puted with the hybrid functional B3LYP/6-31G*,[6,7] is al-
Both 13 and 14 arise from the initial imine 12, which
most coincidental with the solid-state structure, although may add a hydroxy group either intramolecularly giving rise
the latter reveals a different orientation of the hy- to 13 or intermolecularly to another molecule of 12 to pro-
droxymethyl groups involved in intermolecular hydrogen- duce 14 (Scheme 2). The structure of the latter is also sup-
bonding.
ported by its spectroscopic data. With the sole exception of
The large coupling constant between the NH and 2-H the stretching bands for the hydroxy (3600–3000 cm–1) and
protons in compounds 6–11 (ca. 11–12 Hz) points to an amino (3280–3250 cm–1) groups, the IR spectrum does not
axial disposition of the N–H proton in solution, identical show any signal above 1617 cm–1. The H and 13C NMR
1
to that in the solid-state structure of 6, which is inferred spectra recorded in [D6]DMSO show two signal sets in con-
from the dihedral angle H–N–C–H (ca. 154°) and consis- trast to 13. The presence of two protons at δ = 5.67 and
tent with an E1 conformation of the oxazolidine moiety 5.21 ppm along with their corresponding carbon reso-
(Figure 1).[8]
nances at δ = 94.12 and 94.71 ppm (Figure 3) is consistent
As in TRIS-based oxazolidines generated from aldehydes with the typical shifts found for a hemiaminal ether, that is,
bearing electron-withdrawing groups, the above-mentioned combining an open fragment and a cyclic oxazolidine.
arrangement reflects a strong anomeric effect. This is sup-
ported by a shorter N–C2 bond (1.473 Å) relative to the N– tence of three diastereotopic methylenes centered at δ = 4.14
C4 length (1.491 Å) in compound 6, both in the crystal and (Jgem = 8.5 Hz), 4.07 (Jgem = 8.5 Hz), and 3.79 ppm (Jgem
computationally-determined structures (Figure 2, Table S1 10.5 Hz), which correlate with carbon resonances at δ =
in the Supporting Information). 75.13, 72.82, and 65.56 ppm, respectively. The acyclic hy-
The oxazolidine moiety also manifests itself by the exis-
=
In addition, the stability associated with the nǞσ* inter- droxymethylene fragment shows a singlet signal at δ =
action was measured by NBO analysis of the optimized ge- 3.25 ppm (6 H) that correlates with the carbon signal at δ
ometry of 6. The strongest interaction involves the lone pair = 63.99 ppm (3 C). Furthermore, the mass spectrum (Fig-
on the nitrogen atom (LPN) as donor and the σ*C2–O1 or- ure S1) does not exhibit any line attributable to the molecu-
bital as acceptor fragment (Table 1).
lar peak, although the fragmentation pattern supports the
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R. F. Martínez et al.
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Scheme 2.
Scheme 3.
Accordingly, basic substituents susceptible to proton-
ation play the role of an electron-withdrawing group cap-
able of activating the aldehyde function. Thus, the conden-
sation of 1 with 5-(4-formylphenyl)pyrimidine led to the
corresponding oxazolidine 15 in almost quantitative yield
(98%).
Figure 3. Heteronuclear multiple quantum correlation (HMQC) ex-
periment in 14.
proposed structure. The most important molecular subunits
and their relative intensities are shown in Scheme S1 in the
Supporting Information. The HRMS-CI analysis of the
most abundant fragment (m/z = 400; 100%) is also in com-
plete agreement with the proposed structure for 14.
The facile formation of oxazolidines from formylpyr-
idines or -quinolines should be ascribed to the π-deficient
In stark contrast, the reactions of amino alcohols such
character and basicity of such heterocycles (pKa ≈ 4.77 for as TRIS (1), 2-amino-2-methyl-1,3-propanediol, and 2-
4-formylpyridine[9]).
amino-2-methyl-1-propanol with pyridoxal, N-(3-formyl-2-
In aqueous or hydro-alcoholic solution, these nitrogen- pyridinyl)-2,2-dimethylpropanamide, and 2-amino-3-pyr-
containing rings can be partially protonated, which en- idinecarboxaldehyde afforded iminic structures 16–20 in
hances their reactivity in nucleophilic addition, and they yields of 32–84%.
behave as electron-withdrawing benzaldehydes (Schemes 3
and 4).[4] In a similar way, 4-formylpyridine N-oxide would scopic data. The imine function is evidenced by an IR ab-
act as a protonated 4-formylpyridine.
sorption at around 1640 cm–1 (C=N), a singlet signal for
Again, the proposed structures are supported by spectro-
Scheme 4.
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Schiff Bases from TRIS and Formylpyridines
the iminic proton at around 8.8 ppm in compounds 16 and
17, and at around 8.4 ppm in 18–20; the iminic carbon reso-
nates at around 161 ppm in all cases. The IR band at
around 1680–1700 cm–1 along with a carbon signal at
around 176 ppm also evidence the amide function in 18 and
19. Finally, the existence of a downfield-shifted singlet at
around 15 ppm in compounds 16 and 17 and at around
12 ppm in the cases of 18 and 19 suggests a strong intramo-
lecular hydrogen bond involving the iminic nitrogen and a
vicinal OH or NH group. The solid-state structures of 19
and 20 were determined by X-ray crystallographic analyses
(Figures 4 and 5)[5] and are in agreement with those inferred
from data in solution.
Figure 5. Thermal ellipsoid plot of imine 20 drawn at the 50%
probability level.
compounds 16–20 contributes to the preservation of the
iminic structure and avoids their further evolution to oxazol-
idines.
Table 2. Hydrogen bonds observed in the crystal structures of 19
and 20.
D–H···A
d(D–H) [Å] d(H···A) [Å] d(D···A) [Å] Є(DHA) [°]
19 O2–H2···O3
O3–H3···N2
O3–H3···O1
0.84
0.84
0.84
0.88
1.92
1.95
2.55
2.16
2.74
2.77
3.07
2.75
162.7
164.2
121.0
124.5
N1–H1···N3
20 N1–H1B···N3
O1–H1O···O2
0.91
0.90
0.92
2.02
1.82
1.80
2.72
2.72
2.72
132.4
174.9
175.0
O2–H2O···N2
Figure 4. ORTEP diagram of imine 19 with ellipsoids drawn at the
50% probability level.
Oxazolidine–Imine Equilibria
Oxazolidines 6–11 and 15 in [D6]DMSO solution are in
Thus, both 19 and 20 show in their crystal structures an equilibrium with the corresponding imines 21–27, the for-
intramolecular hydrogen bond between the NH group at C- mer cyclic structures being prevalent (Ͼ80%). Such equilib-
2 of the pyridine ring and the iminic nitrogen. Moreover, ria can easily be monitored by NMR spectra, which show
there are additional inter- and intramolecular hydrogen bands typical of imines (Table 3): A singlet signal for the
bonds involving other atomic positions (Table 2, Figure 6). iminic proton at around 8.50–9.00 ppm and the C=N reso-
Clearly the presence of intramolecular hydrogen-bonding in nance at around δ = 156–158 ppm.
Figure 6. Extended hydrogen-bonding sheet in the bc plane for compound 20.
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R. F. Martínez et al.
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Table 3. Composition of the oxazolidine–imine equilibria and structure: The IR absorption at 1650 cm–1 (C=N stretching
NMR spectroscopic data of imines 21–27.
band) as well as the proton and carbon resonances at δ =
8.36 and 159.14 ppm are characteristic of the imine func-
tion. H NMR monitoring of the reaction conducted with
deuteriated reagents [C5D5N and (CD3CO)2O] is shown in
Figure 7 and evidences the complete transformation of 6
into 28.
Equilibrium
Population
δ [ppm]
N=CH (mult.)
1
N=CH
6 w 21
7 w 22
8 w 23
9 w 24
10 w 25
11 w 26
15 w 27
96:4
97:3
81:19
89:11
98:2
85:15
91:9
8.44 (s)
8.29 (s)
8.39 (s)
8.67 (s)
9.12 (s)
9.02 (s)
8.51 (s)
158.51
158.48
156.40
157.86
158.01
156.93
158.95
Scheme 5.
The reaction leads quantitatively to 28 after 24 h via the
di-O-acetyl derivative 29 (Scheme 6). The latter is formed
rapidly as the process is essentially complete within 15 min.
Only the resulting imine 28 could be detected at the end.
1
This behavior appears to be general as H NMR monitor-
ing of the acetylation of 10 also evidences the formation of
the diacetyl intermediate, which evolves to produce ulti-
mately the corresponding imine (see Figure S2 in the Sup-
porting Information).
Acetylation Mechanism: Theoretical Rationale
The acetylation protocol begins with the formation of
diacetate 29 by acetylation of two hydroxymethyl groups.
Three possible steps can then take place as depicted in
Scheme 7: a) Attack of acetic anhydride on the endocyclic
Acetylation of 4,4-Bis(hydroxymethyl)-2-(4-pyridyl)-
oxazolidine
To compare the reactivity of the oxazolidines derived oxygen of 29 with concomitant ring-opening of the oxaz-
from formylpyridines against those of substituted benzalde- olidine ring yielding iminium ion 30, which, after deproton-
hydes,[4] we scrutinized the acetylation of 6 with acetic an- ation, releases the per-O-acetylated imine 28, b) attack of
hydride in pyridine, which allowed us to isolate the per-O- the acetylating species on the nitrogen atom of the parent
acetylated imine 28 in 70% yield (Scheme 5). As usual, its oxazolidine to give tetrahedral intermediate 31, which leads
analytical and spectroscopic data are consistent with this to an N-acetyloxazolidine 32 by deprotonation, and c) at-
Figure 7. Evolution of the acetylation of 6 to 28.
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Schiff Bases from TRIS and Formylpyridines
Scheme 6.
Scheme 7. Putative pathways for the acetylation of pyridine-substituted oxazolidines.
tack on the nitrogen atom with simultaneous ring-opening
of the oxazolidine ring to afford oxonium ion 33, which
further adds acetate to give the acetal derivative 34. Alter-
natively, 33 could also be generated by the ring-opening of
31.
Table 4 presents the energies estimated for the above
transformations in pyridine. Calculations with an SMD
(B3LYP/6-31G*) SCRF model to take into account the sol-
vent effect show that the formation of 28 should be the
favored step because the intermediate 30, which leads to 28,
is stabilized by around 16 kcal/mol relative to 31 and 33,
that is, the intermediates that yield the alternative products
32 and 34, respectively. Figure 8 shows the energy profile pyridine.
Figure 8. Schematic energy diagram for the acetylation of 29 in
estimated for these transformations.
ably be attributed to a stabilizing anomeric effect in the ox-
azolidines, a fact also accounting for the greater nucleophi-
licity of the oxygen atom relative to the alternative nitrogen.
Table 4. Energies calculated for the different mechanisms for the
acetylation of 29.[a]
Erel [kcalmol–1]
29 + Ac2O
30 + AcO–
28 + AcOH
31 + AcO–
32 + AcOH
33 + AcO–
34
0.00
+28.63
–5.62
+44.70
–9.76
+48.57
–6.43
Conclusions
Formylpyridines and TRIS react under mild aqueous
conditions to produce 1,3-oxazolidines in good yields. Spec-
troscopic and crystallographic data fully support the struc-
tures of such substances and reflect the existence of a stabi-
lizing anomeric effect. The reaction can also be extended to
[a] Determined at the B3LYP/6-31G* level of theory.
The fact that both N-acetyloxazolidine 32 and acetal 34 formylquinolines, for which the anomalous dimer 14 has
are more stable species than 28 suggests that the latter also been characterized. An evaluation of oxazolidine–
should be the kinetically-controlled product. The differ- imine equilibria in DMSO solution evidences the greater
ences observed between the reaction pathways can presum- stability of the former. Oxazolidines undergo regiospecific
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= 256.7 Hz), 146.6 (d, JC-F = 4.9 Hz), 138.3 (d, JC-F = 23.5 Hz),
136.4 (d, JC-F = 10.9 Hz), 122.4 (C-arom.), 85.8 (d, JC2,F = 1.3 Hz,
C-2), 69.6 (C-5), 67.8 (C-4), 63.0, 62.9 (2 C, CH2) ppm.
C10H13FN2O3 (228.22): calcd. C 52.63, H 5.74, N 12.27; found C
52.69, H 5.66, N 12.22.
ring-opening under acetylating conditions leading to per-O-
acetyl imines. A theoretical study in both the gas phase and
in pyridine points to the intermediacy of an iminium ion as
the preferential pathway, which also accounts for the
greater nucleophilicity of the oxygen atom as the reaction
site.
1
Spectroscopic Data for 22: H NMR (400 MHz, [D6]DMSO): δ =
8.69 (d, J = 5.2 Hz, 1 H, H-arom.), 8.37 (d, J = 4.0 Hz, 1 H, H-
arom.), 8.29 (s, 1 H, CH=N), 8.21 (s, 1 H, H-arom.), 3.62 (s, 6 H,
CH2) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 158.5 (C=N),
151.5, 146.2, 139.3, 130.4, 124.1 (C-arom.), 69.5 (C-N), 62.0 (3 C,
CH2) ppm.
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 FT-IR THERMO spectropho-
tometer. Solid samples were recorded in KBr (Merck) pellets.
NMR spectra were recorded with Bruker 400 and 500 AC/PC in-
struments in different solvent systems. Assignments were confirmed
by homo- and hetero-nuclear double-resonance and DEPT (distor-
tionless enhancement by polarization transfer) experiments. TMS
was used as the internal standard (δ = 0.00 ppm) and all J values
are given in Hz. Microanalyses were performed with a Leco 932
analyzer. High-resolution mass spectra (chemical ionization) were
recorded with an Autospec-Q spectrometer by the Servicio de Es-
pectrometría de Masas de la Universidad de Sevilla (Spain).
4-[4,4-Bis(hydroxymethyl)oxazolidin-2-yl]pyridine N-Oxide (8):
Yield 1.90 g, 51%; m.p. 109–110 °C. IR (KBr): ν
= 3400–3000
˜
max
(OH, NH), 1617, 1491, 1446 (arom.), 1216, 1179 (N–O), 1077,
1
1052, 1021 (C–O, C–N), 871, 851 (py) cm–1. H NMR (400 MHz,
[D6]DMSO): δ = 8.19 (d, J = 6.4 Hz, 2 H, H-arom.), 7.40 (d, J =
6.4 Hz, 2 H, H-arom.), 5.43 (s, 1 H, 2-H), 4.80 (s, 2 H, OH), 3.69
(d, J = 8.0 Hz, 1 H, CH2, ring), 3.64 (d, J = 8.0 Hz, 1 H, CH2,
ring), 3.43 (s, 2 H, CH2), 3.40 (m, 1 H, CH2), 3.31 (m, 1 H, CH2),
3.00 (s, 1 H, NH) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
139.0, 138.8, 124.7 (C-arom.), 89.8 (C-2), 69.7 (C-5), 67.8 (C-4),
63.1 (2 C, CH2) ppm. C10H14N2O4 (226.23): calcd. C 53.09, H 6.24,
N 12.38; found C 52.79, H 6.18, N 12.01.
General Procedure for the Synthesis of 2-(Hetero)aryl-4,4-bis-
(hydroxymethyl)oxazolidines: A solution of the corresponding alde-
hyde (16.5 mmol) in a small volume of methanol was slowly added
1
Spectroscopic Data for 23: H NMR (400 MHz, [D6]DMSO): δ =
8.39 (s, 1 H, CH=N), 8.24 (d, J = 5.2 Hz, 2 H, H-arom.), 7.77 (d,
J = 5.2 Hz, 1 H, H-arom.), 3.60 (s, 6 H, CH2) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 156.4 (C=N), 139.5, 133.7, 125.2 (C-
arom.), 68.6 (C-N), 62.2 (3 C, CH2) ppm.
to
a solution of α,α,α-tris(hydroxymethyl)methylamine (2.0 g,
16.5 mmol) in water (16 mL). The mixture was stirred at room tem-
perature to yield a precipitate within a few minutes. When the mix-
ture did not precipitate spontaneously, it was evaporated in vacuo
to give a solid on standing or on cooling. The resulting product
was collected by filtration, washed successively with cold water, eth-
anol, and diethyl ether, and recrystallized from ethanol or meth-
anol.
4,4-Bis(hydroxymethyl)-2-(3-quinolinyl)oxazolidine (9): Yield 3.74 g,
87%; m.p. 157–158 °C. IR (KBr): ν
= 3268, 3190 (OH, NH),
˜
max
1593, 1501, 1462 (arom.) cm–1. H NMR (500 MHz, [D6]DMSO):
δ = 8.99 (s, 1 H, H-arom.), 8.39 (s, 1 H, H-arom.), 8.05 (d, J =
8.5 Hz, 1 H, H-arom.), 8.02 (d, J = 8.0 Hz, 1 H, H-arom.), 7.77 (t,
J = 8.0 Hz, 1 H, H-arom.), 7.62 (t, J = 7.5 Hz, 1 H, H-arom.), 5.69
(d, J2-H,NH = 10.5 Hz, 1 H, 2-H), 4.87 (t, J = 5.5 Hz, 2 H, OH),
3.84 (d, J = 8.0 Hz, 1 H, CH2, ring), 3.78 (d, J = 8.0 Hz, 1 H, CH2,
1
4,4-Bis(hydroxymethyl)-2-(4-pyridyl)oxazolidine (6): Yield 3.16 g,
91%; m.p. 117–119 °C. IR (KBr): ν
= 3500–3100 (OH, NH),
˜
max
1612, 1488 (arom.) cm–1. 1H NMR (400 MHz, [D6]DMSO): δ =
8.57 (d, J = 4.0 Hz, 2 H, H-arom.), 7.42 (d, J = 4.8 Hz, 2 H, H-
arom.), 5.43 (d, J2-H,NH = 10.8 Hz, 1 H, 2-H), 4.84 (br. s, 2 H, OH),
3.70 (d, J = 8.0 Hz, 1 H, CH2, ring), 3.67 (d, J = 8.0 Hz, 1 H, CH2,
ring), 3.44 (s, 2 H, CH2), 3.41 (d, J = 11.2 Hz, 1 H, CH2), 3.32 (d,
J = 11.2 Hz, 1 H, CH2), 2.96 (d, JNH,2-H = 10.8 Hz, 1 H, NH) ppm.
13C NMR: δ = (100 MHz, [D6]DMSO): 149.6, 149.1, 121.2 (C-
arom.), 90.0 (C-2), 69.1 (C-5), 67.3 (C-4), 62.7, 62.4 (2 C,
CH2) ppm. C10H14N2O3 (210.23): calcd. C 57.13, H 6.71, N 13.33;
found C 57.12, H 6.70, N 13.22.
ring), 3.54 (d, JCH2,OH = 5.5 Hz, 2 H, CH2), 3.52 (dd, JCH2,OH
5.5, JH,H = 11.0 Hz, 1 H, CH2), 3.44 (dd, JCH2,OH = 5.5, JH,H
=
=
11.0 Hz, 1 H, CH2), 3.12 (d, JNH,2-H = 10.5 Hz, 1 H, NH) ppm.
13C NMR (125 MHz, [D6]DMSO): δ = 150.0, 148.0, 133.8, 133.6,
130.1, 129.2, 128.8, 127.7, 127.3 (C-arom.), 90.4 (C-2), 69.8 (C-5),
68.0 (C-4), 63.4, 63.2 (2 C, CH2) ppm. C14H16N2O3 (260.29): calcd.
C 64.60, H 6.20, N 10.76; found C 64.48, H 6.34, N 10.70.
1
Spectroscopic Data for 24: H NMR (400 MHz, [D6]DMSO): δ =
9.36 (d, J = 2.0 Hz, 1 H, H-arom.), 8.67 (s, 1 H, CH=N), 8.64 (d,
J = 1.6 Hz, 1 H, H-arom.), 8.08 (m, 2 H, H-arom.), 7.83 (m, 1 H,
H-arom.), 7.66 (m, 1 H, H-arom.), 4.54 (t, J = 5.6 Hz, 3 H, OH),
3.68 (d, J = 5.6 Hz, 6 H, CH2) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 157.9 (C=N), 148.7, 136.4, 130.9, 130.0, 129.3, 127.8
(C-arom.), 68.6 (C-N), 62.2 (3 C, CH2) ppm.
1
Spectroscopic Data for 21: H NMR (400 MHz, [D6]DMSO): δ =
8.44 (s, 1 H, CH=N), 8.64 (d, J = 5.6 Hz, 2 H, H-arom.), 7.71 (d,
J = 5.6 Hz, 2 H, H-arom.), 3.62 (s, 6 H, CH2) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 158.5 (C=N), 150.5, 123.7, 122.3 (C-
arom.), 68.8 (C-N), 62.0 (3 C, CH2) ppm.
2-(3-Fluoropyridin-4-yl)-4,4-bis(hydroxymethyl)oxazolidine
(7): 4,4-Bis(hydroxymethyl)-2-(4-quinolinyl)oxazolidine
(10):
Yield
Yield 3.38 g, 90%; m.p. 102–103 °C. IR (KBr): ν = 3400–3000
2.41 g, 56%; m.p. 149–150 °C. IR (KBr): ν = 3512, 3453, 3291,
3136 (OH, NH), 1593, 1577, 1510, 1467, 1439, 768 (arom.), 1054,
˜
˜
max
max
(OH, NH), 1617, 1571 (arom.), 1078, 1057 (C–O) cm–1. H NMR
(400 MHz, [D6]DMSO): δ = 8.54 (d, J = 2.0 Hz, 1 H, H-arom.), 1002 (C–O, C–N) cm–1. 1H NMR (400 MHz, [D6]DMSO): δ = 8.93
8.46 (dd, J = 0.8, J = 4.8 Hz, 1 H, H-arom.), 7.59 (t, J = 6.0 Hz, (d, J = 4.4 Hz, 1 H, H-arom.), 8.35 (d, J = 8.4 Hz, 1 H, H-arom.),
1
1 H, H-arom.), 5.69 (s, 1 H, 2-H), 4.81 (t, J = 6.0 Hz, 1 H, OH), 8.05 (d, J = 8.4 Hz, 1 H, H-arom.), 7.77 (t, J = 8.0 Hz, 1 H, H-
4.80 (t, J = 6.0 Hz, 1 H, OH), 3.76 (d, J = 7.8 Hz, 1 H, CH2, ring), arom.), 7.71 (d, J = 4.4 Hz, 1 H, H-arom.), 7.63 (d, J = 8.0 Hz, 1
3.70 (d, J = 7.8 Hz, 1 H, CH2, ring), 3.46 (d, JCH2,OH = 5.6 Hz, 2
H, H-arom.), 6.08 (d, J2-H,NH = 11.2 Hz, 1 H, 2-H), 4.92 (t, J =
H, CH2), 3.43 (dd, JCH2,OH = 5.6, JH,H = 11.2 Hz, 1 H, CH2), 3.36 5.6 Hz, 1 H, OH), 4.85 (t, J = 5.6 Hz, 1 H, OH), 3.84 (s, 2 H, CH2,
(dd, JCH2,OH = 5.6, JH,H = 11.2 Hz, 1 H, CH2), 3.08 (s, 1 H,
ring), 3.58 (d, JCH2,OH = 5.6 Hz, 2 H, CH2), 3.48 (dd, JCH2,OH
=
=
NH) ppm. 13C NMR: δ = (100 MHz, [D6]DMSO): 157.5 (d, JC-F 6.0, JH,H = 11.2 Hz, 1 H, CH2), 3.43 (dd, JCH2,OH = 5.6, JH,H
6230
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6224–6232

Schiff Bases from TRIS and Formylpyridines
11.2 Hz, 1 H, CH2), 3.07 (d, JNH,2-H = 11.2 Hz, 1 H, NH) ppm.
(dd, JCH2,OH = 4.0, JH,H = 10.5 Hz, 1 H, CH2), 3.74 (dd, JCH2,OH =
13C NMR (100 MHz, [D6]DMSO): δ = 150.9, 148.2, 145.7, 129.7, 4.0, JH,H = 10.5 Hz, 1 H, CH2), 3.25 (s, 6 H, CH2), 1.29 (br. s, 2
129.7, 126.8, 125.9, 125.7, 117.8 (C-arom.), 88.8 (C-2), 69.2 (C-5), H, NH) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 159.6–119.6
68.2 (C-4), 63.4, 62.7 (2 C, CH2) ppm. C14H16N2O3 (260.29): calcd.
C 64.60, H 6.20, N 10.76; found C 64.45, H 6.19, N 10.97.
(C-arom.), 94.7 (OCHN), 94.1 (C-2), 75.1 (CH2), 74.6 (C-N), 72.8
(CH2), 65.6 (CH2), 64.0 (3 C, CH2), 57.1 (C-N) ppm. HRMS (CI):
calcd. for C24H22N3O3 400.1661; found 400.1662.
+
1
Spectroscopic Data for 25: H NMR (400 MHz, [D6]DMSO): δ =
4,4-Bis(hydroxymethyl)-2-[4-(pyrimidin-5-yl)phenyl]oxazolidine (15):
9.12 (s, 1 H, CH=N), 9.01 (d, J = 4.4 Hz, 1 H, H-arom.), 8.85 (d,
J = 8.4 Hz, 1 H, H-arom.), 8.10 (d, J = 8.4 Hz, 2 H, H-arom.),
3.74 (s, 6 H, CH2) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
158.0 (C=N), 150.8, 148.9, 139.9, 129.9, 127.8, 125.2, 121.0 (C-
arom.), 69.7 (C-N), 62.3 (3 C, CH2) ppm.
Yield 4.50 g, 95%; m.p. 165–166 °C. IR (KBr): ν
= 3348, 3226
˜
max
(OH, NH), 1574, 1552, 1490 (arom.) cm–1. 1H NMR (500 MHz,
[D6]DMSO): δ = 9.20 (s, 1 H, H-arom.), 9.16 (s, 1 H, H-arom.),
7.82 (d, J = 8.5 Hz, 2 H, H-arom.), 7.60 (d, J = 8.0 Hz, 2 H, H-
arom.), 5.45 (d, J2-H,NH = 11.0 Hz, 1 H, 2-H), 4.87 (t, J = 5.5 Hz,
1 H, OH), 4.76 (t, J = 5.5 Hz, 1 H, OH), 3.74 (d, J = 7.5 Hz, 1 H,
CH2, ring), 3.70 (d, J = 7.5 Hz, 1 H, CH2, ring), 3.49 (dd, JCH2,OH
= 6.0, JH,H = 11.0 Hz, 1 H, CH2), 3.46 (d, JCH2,OH = 5.5 Hz, 2 H,
CH2), 3.43 (dd, JCH2,OH = 6.0, JH,H = 11.0 Hz, 1 H, CH2), 2.83 (d,
JNH,2-H = 11.0 Hz, 1 H, NH) ppm. 13C NMR (125 MHz, [D6]-
DMSO): δ = 157.8, 155.2, 141.7, 134.2, 133.4, 127.7, 127.3 (C-
arom.), 91.6 (C-2), 69.6 (C-5), 67.8 (C-4), 63.6, 62.9 (2 C,
CH2) ppm. C15H17N3O3 (287.31): calcd. C 62.71, H 5.96, N 14.63;
found C 62.59, H 5.99, N 14.75.
4-Hydroxymethyl-4-methyl-2-(4-quinolinyl)oxazolidine (11): From
2-amino-2-methyl-1,3-propanediol and following the same pro-
cedure as used for 10, compound 11 was isolated (1.09 g, 27%) as
a mixture of diastereomers 11a and 11b (ratio 54:46; m.p. 102–
103 °C). IR (KBr): νmax = 3477, 3262, 3226 (OH, NH), 1597, 1569,
˜
1509, 766 (arom.), 1111, 1057, 1006 (C–O, C–N) cm–1. C14H16N2O2
(244.29): calcd. C 68.83, H 6.60, N 11.47; found C 68.66, H 6.65,
N 11.24.
Spectroscopic Data for 11a: 1H NMR (400 MHz, [D6]DMSO): δ =
8.91 (s, 1 H, H-arom.), 8.32 (t, J = 8.4 Hz, 1 H, H-arom.), 8.04
(dd, J = 4.4, J = 8.0 Hz, 1 H, H-arom.), 7.77 (dd, J = 7.3, J =
10.8 Hz, 1 H, H-arom.), 7.71 (d, J = 3.8 Hz, 1 H, H-arom.), 7.63
1
Spectroscopic Data for 27: H NMR (400 MHz, [D6]DMSO): δ =
9.25 (s, 1 H, H-arom.), 9.15 (s, 1 H, H-arom.), 8.51 (s, 1 H, CH=N),
8.07 (s, 1 H, H-arom.), 7.92 (d, J = 4.8 Hz, 4 H, H-arom.), 4.48 (t,
J = 5.6 Hz, 3 H, OH), 3.63 (d, J = 5.6 Hz, 6 H, CH2) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 159.0 (C=N), 157.9, 155.7,
137.8, 135.7, 130.7, 129.2 (C-arom.), 68.1 (C-N), 62.4 (3 C,
CH2) ppm.
(dd, J = 6.6, J = 13.4 Hz, 1 H, H-arom.), 6.12 (d, J2-H,NH
=
12.0 Hz, 1 H, 2-H), 4.93 (m, 1 H, OH), 3.91 (d, J = 7.2 Hz, 1 H,
CH2, ring), 3.52 (d, J = 5.6 Hz, 1 H, CH2, ring), 3.30 (d, JCH2,OH
= 4.4 Hz, 1 H, CH2), 3.12 (d, JNH,2-H = 11.6 Hz, 1 H, NH), 1.25
(s, 3 H, CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 150.9–
117.5 (C-arom.), 88.4 (C-2), 72.9 (C-5), 65.5 (CH2), 64.1 (C-4), 22.3
(CH3) ppm.
2-Methyl-2-(pyridoxylideneamino)propane-1,3-diol (16): Starting
from 2-amino-2-methyl-1,3-propanediol, diol 16 was obtained by
following the general procedure; yield 3.10 g, 74%; m.p. 180–
Spectroscopic Data for 11b: 1H NMR (400 MHz, [D6]DMSO): δ =
8.91 (s, 1 H, H-arom.), 8.32 (t, J = 8.4 Hz, 1 H, H-arom.), 8.04
(dd, J = 4.4, J = 8.0 Hz, 1 H, H-arom.), 7.77 (dd, J = 7.3, J =
10.8 Hz, 1 H, H-arom.), 7.71 (d, J = 3.8 Hz, 1 H, H-arom.), 7.63
181 °C. IR (KBr): νmax = 3400–3100 (OH), 1643 (C=N), 1580, 1532
˜
1
(arom.), 1061 (C–O) cm–1. H NMR (400 MHz, [D6]DMSO): δ =
15.31 (s, 1 H, OH-arom.), 8.83 (s, 1 H, CH=N), 7.76 (s, 1 H, H-
arom.), 5.34 (s, 1 H, HO-CH2-arom.), 4.95 (s, 2 H, OH), 4.63 (s, 2
H, CH2-arom.), 3.52 (d, J = 3.2 Hz, 4 H, 2 CH2), 2.35 (s, 3 H,
CH3-arom.), 1.22 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 161.4 (C=N), 157.6, 150.2, 135.8, 133.1, 118.5 (C-
arom.), 65.7 (2 C, CH2), 65.4 (C-N), 59.0 (CH2-arom.), 19.3, 18.2
(2 C, CH3) ppm. C12H18N2O4 (254.28): calcd. C 56.68, H 7.13, N
11.02; found C 56.47, H 7.10, N 10.80.
(dd, J = 6.6, J = 13.4 Hz, 1 H, H-arom.), 6.09 (d, J2-H,NH
=
12.0 Hz, 1 H, 2-H), 4.93 (m, 1 H, OH), 3.86 (d, J = 7.2 Hz, 1 H,
CH2, ring), 3.52 (d, J = 5.6 Hz, 1 H, CH2, ring), 3.48 (dd, JCH2,OH
= 7.2, JH,H = 14.4 Hz, 1 H, CH2), 3.39 (dd, JCH2,OH = 5.6, 14.4 Hz,
1 H, CH2), 3.26 (d, JNH,2-H = 11.2 Hz, 1 H, NH), 1.13 (s, 3 H,
CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 150.9–117.5 (C-
arom.), 89.1 (C-2), 73.1 (C-5), 66.1 (CH2), 64.1 (C-4), 22.3
(CH3) ppm.
2-Methyl-2-(pyridoxylideneamino)propan-1-ol (17): Starting from 2-
amino-2-methyl-1-propanol, propanol 17 was obtained by follow-
ing the same procedure as used for 16; yield 3.15 g, 80%; m.p. 178–
1
Spectroscopic Data for 26: H NMR (400 MHz, [D6]DMSO): δ =
9.02 (s, 1 H, CH=N), 9.00 (d, J = 3.6 Hz, 1 H, H-arom.), 8.35–764
(m, 5 H, H-arom.), 3.54 (s, 6 H, CH2) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 156.9 (C=N), 150.9–111.8 (C-arom.), 66.8 (C-N),
66.2 (3 C, CH2) ppm.
179 °C. IR (KBr): νmax = 3368, 3077 (OH), 1633 (C=N), 1560, 1511
˜
1
(arom.), 1073, 1036, 1016 (C–O, C–N) cm–1. H NMR (400 MHz,
[D6]DMSO): δ = 15.26 (s, 1 H, OH-arom.), 8.81 (s, 1 H, CH=N),
7.80 (s, 1 H, H-arom.), 5.37 (s, 1 H, HO-CH2-arom.), 5.06 (s, 1 H,
OH), 4.65 (s, 2 H, CH2-arom.), 3.40 (s, 2 H, CH2), 2.35 (s, 3 H,
CH3-arom.), 1.27 (s, 6 H, 2 CH3) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 160.4 (C=N), 156.8, 149.8, 136.4, 133.2, 118.8 (C-
arom.), 69.4 (2 C, CH2), 61.7 (C-N), 58.9 (CH2-arom.), 23.9 (CH3),
19.2 (2 C, CH3) ppm. C12H18N2O3 (238.28): calcd. C 60.49, H 7.61,
N 11.76; found C 60.46, H 7.40, N 11.49.
4-[6Ј-Hydroxy-5Ј,5Ј-bis(hydroxymethyl)-3Ј-(2-quinolinyl)-4Ј-aza-2Ј-
oxahexyl]-4-hydroxymethyl-2-(2-quinolinyl)oxazolidine (14): Yield
0.43 g, 10%; m.p. 164–165 °C. IR (KBr): ν
= 3594, 3453 (OH,
˜
max
NH), 1599, 1560, 1503, 1467 (arom.) cm–1. 1H NMR (500 MHz,
[D6]DMSO): δ = 8.33 (d, J = 8.5 Hz, 1 H, H-arom.), 8.19 (d, J =
8.5 Hz, 1 H, H-arom.), 7.86 (d, J = 8.5 Hz, 1 H, H-arom.), 7.77 (d,
J = 9.5 Hz, 1 H, H-arom.), 7.75 (d, J = 8.5 Hz, 1 H, H-arom.),
2-Hydroxymethyl-2-{2-[(2,2-dimethylpropanoyl)amino]-3-pyridyl-
7.67 (d, J = 8.5 Hz, 1 H, H-arom.), 7.42 (d, J = 7.5 Hz, 1 H, H- methyleneamino}propane-1,3-diol (18): Yield 3.11 g, 61%; m.p. 183–
arom.), 7.39 (d, J = 7.5 Hz, 1 H, H-arom.), 7.35 (t, J = 7.5 Hz, 1 H,
H-arom.), 7.29 (t, J = 7.5 Hz, 1 H, H-arom.), 7.12 (d, J = 8.5 Hz, 1
184 °C. IR (KBr): ν
= 3447 (OH), 1680, 1580 (amide), 1644
˜
max
(C=N), 1604, 1514, 1480, 1450 (arom.) cm–1. H NMR (400 MHz,
1
H, H-arom.), 6.87 (d, J = 8.5 Hz, 1 H, H-arom.), 5.67 (s, 1 H, 2- [D6]DMSO): δ = 11.92 (s, 1 H, NH-arom.), 8.47 (s, 1 H, CH=N),
H), 5.28 (br. s, 1 H, OH), 5.21 (s, 1 H, OCHN), 4.41 (d, J = 9.0 Hz,
1 H, CH2), 4.34 (br. s, 3 H, OH), 4.22 (d, J = 8.5 Hz, 1 H, CH2),
3.91 (d, J = 8.5 Hz, 1 H, CH2), 3.87 (d, J = 8.5 Hz, 1 H, CH2), 3.83
8.36 (dd, J = 1.6, J = 4.8 Hz, 1 H, H-arom.), 8.03 (dd, J = 2.0, J
= 7.6 Hz, 1 H, H-arom.), 7.20 (dd, J = 4.8, J = 7.6 Hz, 1 H, H-
arom.), 4.58 (t, J = 5.6 Hz, 3 H, 3 OH), 3.67 (d, J = 5.6 Hz, 6 H,
Eur. J. Org. Chem. 2010, 6224–6232
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6231

R. F. Martínez et al.
FULL PAPER
3 CH2), 1.25 (s, 9 H, 3 CH3) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 176.2 (C=O), 161.8 (C=N), 151.4, 149.5, 141.4, 119.1
(C-arom.), 69.3 (C-N), 61.9 (CH2), 40.4 (C-CO), 27.8 (CH3) ppm.
C15H23N3O4 (309.36): calcd. C 58.24, H 7.49, N 13.58; found C
57.96, H 7.58, N 13.59.
CH3, OAc) ppm. HRMS-CI(C16H21N2O6[M + H]+): Calculated:
337.1400; found 337.1412.
Supporting Information (see also the footnote on the first page of
1
this article): Figures S1 and S2, Scheme S1, Table S1, H and 13C
NMR spectra, and computational data.
2-Methyl-2-{2-[(2,2-dimethylpropanoyl)amino]-3-pyridylmethylen-
amino}propane-1,3-diol (19): Starting from 2-amino-2-methyl-1-
propanol, diol 19 was obtained by following the same procedure as
Acknowledgments
used for 18; yield 4.07 g, 84%; m.p. 173–174 °C. IR (KBr): ν
=
˜
max
This work was supported by the Junta de Extremadura
(PRI08A032), the Ministerio de Educación y Ciencia (MEC) and
Fondos Europeos para el Desarrollo Regional (FEDER)
(CTQ2007-66641 and CTQ 2010-18938). R. F. M. thanks the Junta
de Extremadura for a fellowship.
3400–3100 (OH), 1697, 1579 (amide), 1643 (C=N), 1602, 1509,
1479, 1446 (arom.) cm–1. 1H NMR (400 MHz, [D6]DMSO): δ =
11.92 (s, 1 H, NH-arom.), 8.39 (s, 1 H, CH=N), 8.36 (dd, J = 1.6,
J = 4.8 Hz, 1 H, H-arom.), 8.06 (dd, J = 2.0, J = 7.6 Hz, 1 H, H-
arom.), 7.20 (dd, J = 4.8, J = 7.6 Hz, 1 H, H-arom.), 4.69 (t, J =
5.6 Hz, 2 H, 2 OH), 3.57 (dd, J = 6.0, J = 10.8 Hz, 2 H, CH2),
3.50 (dd, J = 5.6, J = 10.4 Hz, 2 H, CH2), 1.26 (s, 9 H, 3 CH3),
1.22 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
176.1 (C=O), 160.5 (C=N), 151.5, 149.5, 141.3, 119.1, 119.1 (C-
arom.), 66.5 (C-N), 66.1 (CH2), 40.4 (C-CO), 27.8, 18.7
(CH3) ppm. C15H23N3O3 (293.36): calcd. C 61.41, H 7.90, N 14.32;
found C 61.32, H 7.81, N 14.05.
[1] a) E. D. Bergmann, Chem. Rev. 1953, 53, 309–352; b) L. Lázár,
F. Fülöp, Eur. J. Org. Chem. 2003, 3025–3042.
[2] M. Senkus, J. Am. Chem. Soc. 1945, 67, 1515–1519.
[3] J. S. Pierce, C. D. Lunsford, R. W. Raiford Jr., J. L. Rush, D. W.
Riley, J. Am. Chem. Soc. 1951, 73, 2595–2596.
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Chem., DOI: ejoc.201000636, in press.
[5] CCDC-781891 (for 6), -781893 (for 19) and -781892 (for 20)
contains the supplementary crystallographic data for this pa-
per. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
2-(2-Amino-3-pyridylmethyleneamino)-2-methylpropane-1,3-diol
(20): Starting from 2-amino-2-methyl-1-propanol, diol 20 was ob-
tained by following the same procedure as used for 18; yield 1.10 g,
32%; m.p. 118–119 °C. IR (KBr): ν
= 3466, 3337 (OH, NH),
˜
max
1633 (C=N), 1597, 1577, 1556, 1450 (arom.) cm–1 1H NMR
.
(400 MHz, [D6]DMSO): δ = 8.38 (s, 1 H, CH=N), 7.98 (d, J =
4.8 Hz, 1 H, H-arom.), 7.81 (br. s, 2 H, NH2), 7.64 (d, J = 7.2 Hz,
1 H, H-arom.), 6.60 (dd, J = 4.8, J = 7.8 Hz, 1 H, H-arom.), 4.63
(t, J = 5.6 Hz, 2 H, 2 OH), 3.51 (dd, J = 5.6, J = 10.8 Hz, 2 H,
CH2), 3.42 (dd, J = 5.6, J = 10.4 Hz, 2 H, CH2), 1.15 (s, 3 H,
CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 160.5 (C=N),
158.4, 149.8, 141.6, 113.1, 111.7 (C-arom.), 66.5 (CH2), 65.2 (C-
N), 18.8 (CH3) ppm. C10H15N3O2 (209.24): calcd. C 57.40, H 7.23,
N 20.08; found C 57.16, H 7.31, N 19.99.
[6] a) A. D. Becke, J. Chem. Phys. 1993, 98, 5648–5652; b) C. Lee,
W. Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785–789.
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M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B.
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nenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hase-
gawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai,
T. Vreven, J. A. Montgomery Jr., J. E. Peralta, F. Ogliaro, M.
Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Starov-
erov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell,
J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M.
Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Ad-
amo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev,
A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Mar-
tin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador,
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Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian 09,
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1,3-Diacetoxy-2-acetoxymethyl-2-(4-pyridylmethyleneamino)-
propane (28): Acetic anhydride (6.5 mL) was added to a solution
of the oxazolidine 6 (1.05 g, 5.0 mmol) in pyridine (6.7 mL). The
reaction mixture was kept at 0 °C for 24 h and then it was poured
into ice–water. The resulting product was extracted with chloro-
form (3 ϫ50 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 to yield compound 28 as an oil
[8] a) J. F. Stoddart, Stereochemistry of Carbohydrates, Wiley, New
York, 1971, pp. 137–139; b) J. F. Stoddart, Stereochemistry of
Carbohydrates, Wiley, New York, 1971, pp. 97–102.
[9] A. R. Katritzky, C. W. Rees, Comprehensive Heterocyclic Chem-
istry (Eds.: A. J. Boulton, A. McKillop), Pergamon Press, Ox-
ford, 1984, vol. 2, pp. 170–171.
(1.18 g, 70%). IR (NaCl): ν
= 1742 (C=O), 1650 (C=N), 1600,
˜
max
1560, 1466 (arom.) cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.73
(d, J = 5.6 Hz, 2 H, H-arom.), 8.36 (s, 1 H, CH=N), 7.63 (d, J =
5.6 Hz, 2 H, H-arom.), 4.39 (s, 6 H, CH2), 2.07 (s, 9 H, OAc) ppm.
13C NMR (100 MHz, CDCl3): δ = 170.5 (C=O), 159.1 (C=N),
150.3, 142.7, 122.1 (C-arom.), 64.2 (C-N), 63.4 (CH2), 20.8 (3 C,
Received: June 28, 2010
Published Online: September 22, 2010
6232
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Eur. J. Org. Chem. 2010, 6224–6232