Novel 2,5-Disubstituted 1,3-dioxanes and oxazolidines as potential chemoprevention agents and building blocks for organic synthesis

Article abstract of DOI:10.1002/ejoc.201000339

2,5-Disubstituted 1,3-dioxacycloalkanes have recently been found to be promising lead, compounds that possess potent anti-inflammatory activity and therefore may act as chemoprevention agents. Encouraged by this we have designed and synthesized a new seri

Full text of DOI:10.1002/ejoc.201000339

FULL PAPER
DOI: 10.1002/ejoc.201000339
Novel 2,5-Disubstituted 1,3-Dioxanes and Oxazolidines as Potential
Chemoprevention Agents and Building Blocks for Organic Synthesis
Anne J. Rüger,[a] Martin Nieger,[b] Mazen Es-Sayed,[c] and Stefan Bräse*[a]
Keywords: Cyclization / Heterocycles / Chemoprevention / Dioxanes / Oxazolidines / Acetalization
2,5-Disubstituted 1,3-dioxacycloalkanes have recently been
found to be promising lead compounds that possess potent
anti-inflammatory activity and therefore may act as chemo-
prevention agents. Encouraged by this we have designed
and synthesized a new series of 5-amino-2-heteroaryl-1,3-di-
oxanes. Starting from N-protected 2-aminopropane-1,3-diol
and the corresponding aromatic aldehydes, the products
were isolated without isomeric inversion at the deprotection
step. This is the first broadly applicable synthetic approach
to the acetalization of heteroaromatic aldehydes to give 5-
amino-1,3-dioxanes. Our route provides a mild access to both
isomers of this kind of dioxane, that is, cis and trans products,
as well as 4-(hydroxymethyl)-2-heteroaryloxazolidines,
which are useful building blocks in organic synthesis.
Introduction
Cancer is a leading cause of death worldwide and in this
context the development of chemoprevention agents,[1] used
to prevent or inhibit the development of carcinogenesis,[2]
is very important. Non-steroidal anti-inflammatory drugs
(NSAIDS) appear to be useful in the prevention and sup-
pression of colorectal, gastric as well as other types of can-
cer.[3,4] For example, celecoxib has been successfully used in
the treatment of patients with familial adenomatous polyp-
osis (FAP) because it reduces the numbers of colon and
rectum polyps and it has also shown promising results in
the prevention of lung cancer in a Phase IIb clinical
trial.[5–7] However, the adverse effects, such as gastric bleed-
ing, of some NSAIDS (e.g. aspirin) limit their long-term
application as chemoprevention agents.[8] Hence there is
strong demand for advanced pharmaceutics. Clearly, low
toxicity and high activity at low dosage are also indispens-
able for novel drug candidates. In the field of chemopreven-
tion a new substance class has emerged. Different research
groups have described the great value of 1,3-dioxanes (1–3,
Figure 1) in treating cancer, inflammation and reperfusion
injury.[9–11]
Figure 1. Potential chemoprevention agents with a 1,3-dioxane
scaffold.[9–11]
anti-inflammatory activity than aspirin against xylene-in-
duced ear edema in mice and does not prolong the tail
bleeding time.[11] Because they reported 5-amino-2-(substi-
tuted phenyl)-1,3-dioxanes with electron-withdrawing
groups on the phenyl ring to give the best results, we re-
garded the heterocyclic moiety 4 to have high potential in
drug discovery programs.
Heteroaromatics are widely found in both pharmaceuti-
cals and agrochemicals. Furthermore, the 4-(heteroaryl)cy-
clohexanamine moiety is present in several bioactive sub-
stances that might be effective as therapeutic agents for dia-
betes, benign prostatic hyperplasia and numerous other
diseases. As an example, 11β-hydroxysteroid dehydrogenase
(11β-HSD) inhibitor 5, which has therapeutic potential, is
shown in Figure 2.[12–17]
In the last few years Zhao and co-workers have devel-
oped a series of new anti-inflammatory agents based on the
dioxane scaffold 3, which shows a comparable or higher
[a] Karlsruhe Institute of Technology (KIT), Institute of Organic
Chemistry,
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax: +49-721-608-8581
E-mail: braese@kit.edu
[b] Department of Chemistry, Laboratory of Inorganic Chemistry,
University of Helsinki,
P. O. Box 55, 00014 University of Helsinki, Finland
[c] Bayer CropScience SA,
16 rue Jean Marie Leclair, CP 106, 69266 Lyon Cedex 09,
France
Figure 2. 11β-HSD inhibitor 5[17] and building block 4b-H.
Eur. J. Org. Chem. 2010, 3837–3846
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A. J. Rüger, M. Nieger, M. Es-Sayed, S. Bräse
FULL PAPER
Because dioxanes are mimics of cyclohexanes, 5-amino- on the carbonyl. In addition to using dry reagents and sol-
2-heteroaryl-1,3-dioxanes 4-H are very adjuvant building vents it was essential to work under an inert atmosphere
blocks for the continuative development of future drugs (see because otherwise some oxidized product was obtained as
Figure 2). The introduction of oxygen into the molecules well. The structure of this product, N-oxide 8aЈ-Cbz, was
alters the polarity and stability of the derivatives. This may elucidated by NMR and HRMS. We tried several methods
be helpful for facilitating absorption into the body and for the acetalization in order to improve the ratio between
transportation to the site of pharmacological action. the acetals and the side-products as well as the yield of the
Furthermore, the lability of acetals enables them to act as reaction.[11,31–35] The best results were achieved by using
prodrugs.[18,19] As the pH in cell compartments varies and pTsOH, NBS and sulfamic acid as catalysts in toluene at
consequently the metabolism of acetals, dioxanes may have reflux (Scheme 1). However, unfortunately it was not pos-
advantages over cyclohexanes as drugs. This encouraged us sible to suppress the formation of the oxazolidine com-
once more to find a widely applicable synthetic access to 5- pletely and concurrently obtain acceptable yields of the re-
amino-2-heteroaryl-1,3-dioxanes 4, of which there is little quired acetals 4a-Cbz.
reported in the literature.[20–29] Herein we describe a suitable
route to these achiral 5-amino-1,3-dioxanes.
Because the condensation reaction with aminodiol 6-Cbz
is reversible and occurs largely under thermodynamic con-
trol under the conditions applied, more or less stable acetals
and oxazolidines are in equilibrium.[36] Therefore we de-
cided to use a different protecting group strategy to prevent
formation of the oxazolidine. Because it was not possible
to produce phthalimide 6-Phth and nitro compound 9 in
sufficient purity,[37,38] we examined the cyclization step
using precursors 10 and 11.[39,40] Both ketone 10 and hy-
droxymethyl derivative 11 can easily be converted into the
corresponding amines. However, we were not able to ace-
talize pyridinecarbaldehyde 7a with these diols (Figure 3).
Results and Discussion
Preparation of N-Protected 5-Amino-1,3-dioxanes by
Acetalization of Diol 6 and Heterocyclic Aldehydes 7
Starting from 2-amino-1,3-diol 6-H we were able to find
an appropriate protocol for the acetalization of heterocyclic
aldehydes 7, although it was not possible to convert diol 6-
H directly into acetal 4a-H using conditions similar to those
described in the literature for substituted benzaldehydes.[11]
Therefore Cbz-protected aminodiol 6-Cbz was used as the
starting material for the cyclization step.[30] To develop a
suitable procedure for the synthesis of heterocyclic acetals,
pyridinecarbaldehyde 7a (Scheme 1) was examined first. Al-
dehyde 7a was treated with diol 6-Cbz under Lewis and
Brønsted acid catalysis with the addition of a suitable dry-
ing agent. In this way, both the cis and trans isomers of the
desired acetal 4a-Cbz were obtained although the ratio of
isomers was slightly dependent on the reaction conditions.
Figure 3. Precursors for the acetalization reaction with aldehydes.
With these results in hand we continued to use Cbz-pro-
tected aminodiol 6-Cbz as the starting material for further
acetalizations. To ensure that the developed procedure
would work for different heterocycles, we used pTsOH,
NBS and sulfamic acid as catalysts for the synthesis of pyr-
idine acetals 4b and 4c. We achieved the best results for
both aldehydes by using pTsOH (other results not shown
here). Therefore we continued to use this catalyst for the
synthesis of other heterocyclic acetals. It is quite clear that
acetal formation is strongly dependent upon the substrate
used in the reaction. Although pyrrolecarbaldehyde 7d
(Scheme 2, Table 1, Entry 4) underwent decomposition un-
der the reaction conditions, even if the reaction was carried
out at room temperature or in a different solvent, the other
aldehydes could be transformed into acetals or oxazolid-
ines, although thiophene acetal 4g-Cbz was not that stable.
Interestingly, the cis acetals were formed in preference to
the trans products. This observation has been made pre-
viously for other 1,3-dioxanes. Eliel and co-workers re-
ported a detailed study of the axial (cis) predominance of
polar substituents at the 5-position of 1,3-dioxanes.[41] In
Scheme 1. Acetalization of pyridine-2-carbaldehyde (7a). Reagents
and conditions: a) pTsOH, Na2SO4, CHCl3, THF, room temp.; b)
Cbz-Cl, NEt3, EtOH, 0 °C to room temp., 81%; c) NBS, MgSO4,
toluene, reflux, 52% (1.8:1 cis/trans) 4a-Cbz, 15% 8a-Cbz; d) H2,
Pd/C, MeOH, room temp., 88%.
particular, they discussed the presence of hydrogen-bonding
+
Interestingly, we isolated oxazolidine 8a-Cbz as a by- between the ring and NH3 substituents. The thermo-
product, which means that monoprotection of the amine dynamic stability resulting from these hydrogen bonds is
does not prevent nucleophilic attack of the nitrogen atom also shown by Zhao and co-workers for 5-amino-2-substi-
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Novel 2,5-Disubstituted 1,3-Dioxanes and Oxazolidines
tuted-phenyl-1,3-dioxanes (energy-minimized structures by nium nitrate) and its protected surrogate 4b-Cbz, which
modelling).[11] In this study this finding is supported by the show hydrogen bridges between the NH and ring oxygen
solid-state structures of pyridin-3-yl acetal 4b-H (ammo- atoms with a distance of about 2.7 Å (see Figure 4).
In general we elucidated the configuration of the acetals
by performing NOESY experiments. Unfortunately, this
was not possible for oxazolidines 8-Cbz. As there were
strong cross-peaks between the hydrogen atoms at the 2-
and 5-positions of the ring, the acetal was considered to be
cis; the absence of these signals indicated a trans configura-
tion. The results of these analyses are consistent with those
obtained by X-ray crystallography of both cis and trans iso-
mers of pyridin-3-yl acetals (see Figure 4 and Figure 5).
Scheme 2. Acetalization of heteroaromatic aldehydes 7.
Table 1. Acetalization of heteroaromatic aldehydes 7.
Figure 5. Molecular structure of trans-pyridin-3-yl acetal 4b-Cbz
showing the intramolecular NH–O hydrogen bond (displacement
parameters are drawn at the 50% probability level).
In most cases it was possible to separate the cis and trans
acetals as well as the oxazolidine by-products by simple col-
umn chromatography on silica gel. However, in most cases
the chromatographic separation had to be performed twice,
in particular, for analytical purposes. Only for the furan
acetals 4e-Cbz and 4f-Cbz and the thiophene acetal 4g-Cbz
was it impossible to separate the cis and trans products.
Although inseparable mixtures of the two isomers (cis and
trans) of the oxazolidines 8e-Cbz, 8f-Cbz and 8g-Cbz were
obtained, the reactions of pyridinecarbaldehydes 7a and 7c
as well as the pyrrolecarbaldehyde 7d led to a single dia-
stereomer in a stereoselective reaction (Scheme 2).
Although in general oxazolidines 8 were obtained as
side-products in low yields the diastereomerically pure sur-
rogates 8a-Cbz, 8cЈ-Cbz and 8d-Cbz may have potential as
building blocks in the synthesis of biologically active com-
pounds. The application of oxazolidines is manifold. Some
of them act as fungicides or show antimicrobial ac-
[a] NBS used as catalyst. [b] Decomposition of aldehyde. [c]
cis/trans configurations could not be elucidated.
tivity[42–44] and, in particular, they might be used for the
Figure 4. Crystal packing (space filling model) of cis-pyridine-3-yl acetal 4b-Cbz, projection along the a/b plane (left). Molecular structure
of cis-pyridin-3-yl acetal 4b-Cbz (middle) and the cation of cis-4b-H (right) showing intramolecular NH–O hydrogen bonds (displacement
parameters are drawn at the 50% probability level).
Eur. J. Org. Chem. 2010, 3837–3846
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A. J. Rüger, M. Nieger, M. Es-Sayed, S. Bräse
FULL PAPER
synthesis of various inhibitors of methyltransferase Table 2. Deprotection of heteroaromatic acetals 4-Cbz.
SMYD3, which plays a role in liver, colon and breast can-
cer.[45] Out of 150000 compounds, oxazolidine 12 was iden-
tified by molecular modelling as being capable of binding
to this protein. The structural similarities exhibited by ox-
azolidines 8 and inhibitor 12 are illustrated in Figure 6.
Figure 6. Inhibitor 12 of SMYD3 and building block 8a-Cbz.
Deprotection of N-Protected 5-Amino-1,3-dioxanes 4-Cbz
to Yield Acetals 4-H
Further application of acetals 4 required deprotection of
the amine functionality.[37] The use of Cbz as protecting
group allowed the synthesis of free amino acetals 4-H with-
out isomeric inversion during the deprotection step. Not
only was the configuration of the acetals retained, the de-
protection proceeded in good-to-excellent yields for all ace-
tals (see Table 2) with the exception of the free aminothio-
phene acetal 4g-H, which could not be obtained due to the
instability of its protected precursor 4g-Cbz. Furthermore
it was possible to separate the cis and trans acetal at this
step of the synthesis if this had not been achieved before.
Scheme 3. Deprotection of heteroaromatic acetals 4-Cbz.
Even if mixtures of isomers were employed, the cis to trans
ratio was retained, except for the reaction with furan acetal
4f-Cbz for which a small alteration was observed (Table 2,
Entry 5). This was ascribed to a higher stability and/or reac-
tivity of the trans isomer (Scheme 3).
Conclusions
In this work we have developed a widely applicable syn-
thetic approach to 5-amino-2-heteroaryl-1,3-dioxanes and
4-(hydroxymethyl)-2-heteroaryloxazolidines. Starting from
inexpensive precursors, these products were synthesized in
a short reaction sequence involving simple transformations.
Owing to the uniqueness of their structural properties (in-
cluding a high analogy to bioactive molecules) it would be
worth investigating their use as drugs directly or as building
blocks for the synthesis of pharmaceutics and agrochem-
icals.
In general, the acetals 4-Cbz and 4-H were relatively
stable towards ring-opening, except for the thiophenes 4g-
Cbz and 8g-Cbz, which underwent fast decomposition at
room temperature if in contact with any solvent. Every
other acetal 4-Cbz and 4-H was stable at room temperature
in solvent-free conditions. Storage in slightly acidic media,
for example, methanol or CDCl3, for some days also did
not lead to ring-opening or any other kind of decay of these
acetals. To avoid ring-opening of the acetals 4 during col-
umn chromatography, silica gel enriched with 0.1% calcium
ions (Fluka) may be used rather than basic additives like
triethylamine because under these conditions the separation
is not affected. Furthermore, in the case of the free amino
acetals 4-H, the use of this silica gel leads to nitrates. This
facilitates crystallization and thus we were able to obtain
crystals of acetal 4b-H for X-ray analysis, but it was not
indispensable to avoid decomposition.
Experimental Section
General: All reagents were used as purchased from Sigma–Aldrich,
Thermo Fisher Scientific, ABCR and Alfa Aesar. Solvents were
dried and purified by standard methods prior to use or purchased
in suitable quality. Vials from Macherey–Nagel were used for all
reactions above room temperature (sizes 20–20 and 20–10, in com-
bination with N20 oA and N20 TB/oA-M septa). For TLC, alu-
minium foils layered with silica gel (silica gel 60 F254) produced by
Merck were used. Column chromatography was performed on sil-
ica gel enriched with 0.1% Ca (Fluka) or Geduran Si 60 (Merck)
under flash conditions. NMR spectra were recorded with Bruker
Fortunately the heterocyclic moieties were stable under
the deprotection conditions as well and even the furans 4e-
H and 4f-H could be obtained without significant loss by
hydrogenation.
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Novel 2,5-Disubstituted 1,3-Dioxanes and Oxazolidines
AC 250, Avance 400, Avance DRX 500 and Avance 600 spectrome-
tioned between water (60 mL) and EtOAc (80 mL) and the aqueous
layer was extracted with EtOAc (4ϫ50 mL). The combined organic
layers were dried with Na2SO4, filtered and the solvent was re-
moved under reduced pressure. Column chromatography (silica gel,
CH2Cl2/MeOH, 30:1–20:1, v/v) of the crude product yielded 6-Cbz
(3.66 g, 81%) as a white solid. Rf = 0.31 (CH2Cl2/MeOH = 10:1).
1H NMR (400 MHz, CD3OD): δ = 3.57–3.63 [m, 4 H, CH-
(CH2)2], 3.69 [m, 1 H, CH(CH2)2], 5.08 (s, 2 H, CH2Ph), 7.25–7.38
(m, 5 H, Ar-H) ppm. 13C NMR (100 MHz, CD3OD): δ = 56.0 [+,
CH(CH2)2], 62.3 [–, CH(CH2)2], 67.5 (–, CH2Ph), 128.9 (+, C-
2,6Ar), 129.0 (+, C-4Ar), 129.5 (+, C-3,5Ar), 138.3 (Cquat, C-1Ar),
1
ters. The H and 13C NMR chemical shifts are referenced relative
to the residual proton signal and the central peak of the carbon
multiplet of the deuterated solvent (CDCl3 or [D4]MeOH), respec-
tively. IR spectra were recorded with an IFS 88 Bruker FTIR device
neat or as a mixture with KBr (DRIFT). The absorption bands
were measured in wavenumbers with units of cm–1. The intensities
of the bands are characterized as follows: vs = very strong 0–10%
transmittance (T), s = strong 10–40% T, m = medium 40–70% T,
w = weak 70–90% T, vw = very weak 90–100% T. EI-MS, FAB-
MS, FAB-HRMS and HR-EIMS: spectra were measured with a
Finnigan MAT 95 instrument. Elemental analyses were performed
using an Elementar vario MICRO device.
158.8 (Cquat, C=O) ppm. IR (DRIFT): ν = 3300 [s, ν(OH)], 3062
˜
(m), 3030 [m, νAr(C–H)], 2968 [m, ν(CH2)], 2890 [m, ν(CH2)], 1686
[s, ν(C=O)], 1542 [s, νAr(C=C)], 1255 (s), 1042 [s, ν(C–O)], 695 (m)
cm–1. MS (70 eV, EI): m/z (%) = 225 (8) [M]+, 194 (23) [M –
C2H5O]+, 150 (19), 108 (6), 91 (100) [C7H7]+, 65 (7). HRMS
(C11H15NO4): calcd. 225.1001; found 225.0998. C11H15NO4 (225):
calcd. C 58.66, H 6.71, N 6.21; found C 58.65, H 6.76, N 6.21.
Crystal Structure Determinations: All single-crystal X-ray diffrac-
tion studies were carried out with a Bruker–Nonius Kappa-CCD
diffractometer at 123(2) K using Mo-Kα radiation (λ = 0.71073 Å).
Direct methods (SHELXS-97) were used for structure solution and
refinement was carried out by using SHELXL-97[46] (full-matrix
least-squares on F2). Non-hydrogen atoms were refined anisotropi-
cally; hydrogen atoms were localized by difference electron density
determination and refined using a riding model [H(N) free].
cis-4b-H: Colourless crystals, (C9H13N2O2)+·(NO3)–, M = 243.22,
crystal size 0.40ϫ0.20ϫ0.10 mm, monoclinic, space group P21/c
(No. 14), a = 5.9353(4), b = 23.8424(22), c = 7.5294(6) Å, β =
90.100(6)°, V = 1065.50(15) Å3, Z = 4, ρ(calcd.) = 1.516 Mgm–3,
F(000) = 512, µ = 0.125 mm–1, 19555 reflections (2θmax = 55°), 2442
unique (Rint = 0.026), 163 parameters, 9 restraints, R1 [IϾ2σ(I)] =
0.032, wR2 (all data) = 0.087, S = 1.07, largest diff. peak and hole:
0.316 and –0.237 eÅ–3.
General Procedure for the Synthesis of Acetals and Oxazolidines
(GP A): In a vial, MgSO4 (0.5 g per mmol 6-Cbz), benzyl 1,3-dihy-
droxypropan-2-ylcarbamate (6-Cbz; 1.00 equiv.) and a catalytic
amount of pTsOH (0.05–0.10 equiv.) were suspended in dry toluene
(3 mL per mmol 6–Cbz) under argon and the corresponding alde-
hyde (1.10 equiv.) was added. The vial was sealed and the reaction
mixture was stirred at 110 °C for 12–72 h. After cooling to room
temp., the vial was opened and the suspension partitioned between
water and EtOAc (50 mL per mmol 6-Cbz each). The aqueous layer
was extracted with EtOAc (2ϫ50 mL per mmol 6-Cbz) and the
combined organic layers were dried with Na2SO4 and filtered. After
removing the solvent under reduced pressure the crude products
were purified by two-fold column chromatography (silica gel,
CH2Cl2/MeOH, 100:1–30:1, v/v) to obtain the pure title com-
pounds.
cis-4b-Cbz: Colourless crystals, C17H18N2O4, M = 314.33, crystal
size 0.30ϫ0.12ϫ0.08 mm, trigonal, space group R-3 (No. 148), a
= b = 41.377(6), c = 5.263(1) Å, α = β = 90°, γ = 120°, V =
7803(2) Å3, Z = 18, ρ(calcd.) = 1.204 Mgm–3, F(000) = 2988, µ =
0.087 mm–1, 28746 reflections (2θmax = 55°), 3949 unique (Rint
=
General Procedure for the Deprotection of Acetals (GP B): The cor-
responding acetal (1.00 equiv.) and palladium (10 wt.-% on acti-
vated carbon, 0.05–0.10 equiv.) were suspended in MeOH (10 mL
per mmol acetal) and stirred under hydrogen. After filtration
through a plug of Celite®, the solvent was removed under reduced
pressure. The product was purified by column chromatography (sil-
ica gel, CH2Cl2/MeOH, 30:1–10:1, v/v) when necessary.
0.046), 211 parameters, 1 restraint, R1 [IϾ2σ(I)] = 0.057, wR2 (all
data) = 0.163, S = 1.03, largest diff. peak and hole: 0.561 and
–0.286 eÅ–3.
The structure contains solvent-accessible voids of 1069.4 Å3 in to-
tal. This void/cavity is approx. 13.7% of the unit cell volume (po-
rosity).[47] There is no solvent inside the cavity. The packing index
is 61.9.[48]
Benzyl 2-(Pyridin-2-yl)-1,3-dioxan-5-ylcarbamate (4a-Cbz): Pre-
pared by slightly modified GP A, NBS was used as the catalyst;
yield up to 52% (1.46 g). cis/trans = 1.8:1.
trans-4b-Cbz: Colourless crystals, C17H18N2O4, M = 314.33, crystal
size 0.40ϫ0.20ϫ0.08 mm, monoclinic, space group P21/n (No.
14), a = 17.878(2), b = 4.882(1), c = 17.996(2) Å, β = 97.21(1)°, V
= 1558.3(4) Å3, Z = 4, ρ(calcd.) = 1.340 Mgm–3, F(000) = 664, µ
cis-4a-Cbz: Rf
=
0.30 (CH2Cl2/MeOH
=
20:1). 1H NMR
3
(400 MHz, CDCl3): δ = 3.78 (d, 3J = 8.8 Hz, 1 H, 5-H), 4.20 (d, J
= 0.096 mm–1, 23003 reflections (2θmax = 55°), 3567 unique (Rint
=
= 1.5 Hz, 4 H, 4,6-H), 5.15 (s, 2 H, CH2Ph), 5.65 (s, 1 H, 2-H),
0.051), 211 parameters, 1 restraint, R1 [IϾ2σ(I)] = 0.052, wR2 (all
data) = 0.113, S = 1.03, largest diff. peak and hole: 0.320 and
–0.322 eÅ–3.
3
5.93 (d, J = 8.8 Hz, 1 H, NH), 7.29–7.40 (m, 6 H, 5,2Ј–6Ј-HAr),
3
4
3
3
7.60 (d, J = 7.7 Hz, 1 H, 3-HAr), 7.74 (ddd, J = 1.6, J = 7.7, J
= 7.7 Hz, 1 H, 4-HAr), 8.63 (d, 3J = 4.7 Hz, 6-HAr) ppm. 13C NMR
(100 MHz, CDCl3): δ = 45.6 (+, C-5), 66.9 (–, CH2Ph), 70.9 (–, C-
4,6), 101.5 (+, C-2), 120.6 (+, C-5Ar), 124.0 (+, C-3Ar), 128.1 (+,
C-2Ј,6ЈAr), 128.1 (+, C-4ЈAr), 128.5 (+, C-3Ј,5ЈAr), 136.3 (Cquat, C-
1ЈAr), 136.9 (+, C-4Ar), 149.1 (+, C-6Ar), 155.8 (Cquat, C=O), 155.9
CCDC-756389 (for cis-4b-H), -756391 (for cis-4b-Cbz) and -756390
(for trans-4b-Cbz) contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(Cquat, C-2Ar) ppm. IR (DRIFT): ν = 3286 [m, ν(OH)], 3052 (m),
˜
Benzyl 1,3-Dihydroxypropan-2-ylcarbamate (6-Cbz):[30] Triethyl-
amine (3.07 mL, 2.23 g, 22.1 mmol) was added to a solution of 2-
aminopropane-1,3-diol (6-H; 1.83 g, 20.1 mmol) in dry ethanol
(15 mL) under argon. The solution was cooled to 0 °C and then
Cbz-Cl (3.14 mL, 3.77 g, 22.1 mmol) was added slowly. The reac-
3002 (m), 2959 [m, ν(CH2)], 2861 [m, ν(CH2)], 1684 [s, ν(C=O)],
1540 [s, νAr(C=C)], 1307 (s), 1182 [s, ν(C–O)], 1105 [s, ν(C–O)],
1080 [s, ν(C–O)], 1044 [s, ν(C–O)], 1001 (m), 780 (s), 745 (s) cm–1.
MS (FAB): m/z (%) = 337 [M + Na]+, 315 (100) [M + H]+, 271,
207 [M – C7H7O]+, 181, 108, 91 [C7H7]+. HRMS (C17H19N2O4):
tion mixture was stirred at room temp. for 2 h. After removing calcd. 315.1345; found 315.1342. C17H18N2O4 (314): calcd. C 64.96,
most of the solvent under reduced pressure the residue was parti-
H 5.77, N 8.91; found C 64.73, H 5.89, N 8.79.
Eur. J. Org. Chem. 2010, 3837–3846
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3841

A. J. Rüger, M. Nieger, M. Es-Sayed, S. Bräse
FULL PAPER
trans-4a-Cbz: Rf = 0.26 (CH2Cl2/MeOH = 20:1). 1H NMR
1
cis-4a-H: Rf = 0.09 (CH2Cl2/MeOH = 10:1). H NMR (400 MHz,
2
(400 MHz, CDCl3): δ = 3.61 (t, 2J = 10.4 Hz, 2 H, 4,6-H), 4.13 CD3OD): δ = 2.81 (mc, 1 H, 5-H), 4.04 (d, J = 11.8 Hz, 2 H, 4,6-
3
2
2
(mc, 1 H, 5-H), 4.38 (dd, J = 3.6, J = 9.9 Hz, 2 H, 4,6-H), 4.71
(mc, 1 H, NH), 5.10 (s, 2 H, CH2Ph), 5.48 (s, 1 H, 2-H), 7.27–7.39
(m, 6 H, 5,2Ј–6Ј-HAr), 7.59 (d, J = 7.7 Hz, 1 H, 3-HAr), 7.74 (dd,
H), 4.22 (d, J = 11.8 Hz, 2 H, 4,6-H), 5.59 (s, 1 H, 2-H), 7.41 (mc,
1 H, 5-HAr), 7.67 (d, 3J = 7.8 Hz, 1 H, 3-HAr), 7.88 (ddd, 4J = 1.6,
3J = 7.7, 3J = 7.8 Hz, 1 H, 4-HAr), 8.52 (d, 3J = 4.8 Hz, 1 H, 6-
3
3J = 7.7, 3J = 7.7 Hz, 1 H, 4-HAr), 8.60 (d, 3J = 4.7 Hz, 6-HAr) ppm. HAr) ppm. 13C NMR (100 MHz, CD3OD): δ = 46.7 (+, C-5), 73.4
13C NMR (100 MHz, CDCl3): δ = 43.6 (+, C-5), 67.1 (–, CH2Ph),
69.9 (–, C-4,6), 101.0 (+, C-2), 120.8 (+, C-5Ar), 124.0 (+, C-3Ar),
(–, C-4,6), 102.7 (+, C-2), 122.8 (+, C-3Ar), 125.8 (+, C-5Ar), 139.1
(+, C-4Ar), 149.5 (+, C-6Ar), 157.5 (Cquat, C-2Ar) ppm. IR (neat): ν
˜
128.2 (+, C-2Ј,6ЈAr), 128.3 (+, C-4ЈAr), 128.6 (+, C-3Ј,5ЈAr), 136.0 = 3364 [w, ν(NH2)], 3283 [w, ν(NH2)], 2969 [w, ν(CH2)], 2916 [w,
(Cquat, C-1ЈAr), 137.0 (+, C-4Ar), 149.0 (+, C-6Ar), 155.6 (Cquat ν(CH2)], 2856 (m), 1593 (m), 1439 (m), 1387 (m), 1235 (w), 1150
C=O), 155.8 (Cquat, C-2Ar) ppm. IR (DRIFT): ν = 3307 [m, [m, ν(C–O)], 1101 [m, ν(C–O)], 1066 [m, ν(C–O)], 1007 (m), 779
,
˜
ν(OH)], 3033 [m, νAr(C–H)], 2958 [m, ν(CH2)], 2874 [m, ν(CH2)],
(m) cm–1. MS (FAB): m/z (%) = 203 [M + Na]+, 181 (100) [M +
1686 [m, ν(C=O)], 1592 [m, νAr(C=C)], 1541 [m, νAr(C=C)], 1390 H]+, 164, 150, 133, 108, 93. HRMS (C9H13N2O2): calcd. 181.0977;
(m), 1311 (m), 1246 (m), 1161 [m, ν(C–O)], 1107 [m, ν(C–O)], 1047 found 181.0975.
[m, ν(C–O)], 1026 (m), 777 (m), 696 (m) cm–1. MS (FAB): m/z (%)
trans-4a-H: Rf
=
0.33 (CH2Cl2/MeOH
=
10:1). 1H NMR
= 337 [M + Na]+, 315 (100) [M + H]+, 271, 217, 137, 108, 91
[C7H7]+. HRMS (C17H19N2O4): calcd. 315.1345; found 315.1342.
C17H18N2O4 (314): calcd. C 64.96, H 5.77, N 8.91; found C 64.85,
H 6.06, N 8.78.
3
(400 MHz, CD3OD): δ = 3.09 (mc, 1 H, 5-H), 3.55 (td, J = 1.4, 2J
= 11.2 Hz, 2 H, 4,6-H), 4.24 (mc, 2 H, 4,6-H), 5.43 (s, 1 H, C-2),
4
3
3
3
7.39 (ddd, J = 1.2, J = 5.0, J = 7.7 Hz, 1 H, 5-HAr), 7.61 (d, J
4
3
3
= 7.7 Hz, 1 H, 3-HAr), 7.85 (ddd, J = 1.7, J = 7.7, J = 7.7 Hz,
1 H, 4-HAr), 8.50 (ddd, 5J = 0.9, 4J = 1.7, 3J = 4.9 Hz, 1 H, 6-
Benzyl 4-(Hydroxymethyl)-2-(pyridin-2-yl)oxazolidine-3-carboxylate
(8a-Cbz): Prepared by slightly modified GP A, NBS used as the
catalyst; yield up to 15% (104 mg). Rf = 0.18 (CH2Cl2/MeOH =
H
Ar) ppm. 13C NMR (100 MHz, CD3OD): δ = 45.3 (+, CH-5),
74.1 (–, C-4,6), 102.0 (+, C-2), 122.6 (+, C-5Ar), 125.8 (+, C-3Ar),
139.1 (+, C-4Ar), 149.6 (+, C-6Ar), 157.7 (Cquat, C-2Ar) ppm. IR
1
20:1). H NMR (400 MHz, CDCl3): δ = 3.64–4.02 (m, 3.5 H, 4-H,
CH2, OH), 4.41 (mc, 2 H, CH2), 5.00 (mc, 2 H, CH2Ph), 6.13 (s,
1 H, 2-H), 6.86 (mc, 1.5 H, Ar-H, OH), 7.11–7.47 (m, 6 H, Ar-H),
7.64 (mc, 1 H, Ar-H), 8.57 (mc, 1 H, Ar-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 59.3 (+, C-4), 64.1 (–, CH2OH), 67.3 (–,
C-5), 68.3 (CH2Ph), 90.5 (+, C-2), 121.6 (+, C-3Ar), 123.6 (+, C-
(neat): ν = 3363 [w, ν(NH )]), 2966 [w, ν(CH )], 2917 [w, ν(CH )],
˜
2
2
2
2846 (m), 1594 (m), 1385 (m), 1141 [m, ν(C–O)], 1088 [s, ν(C–O)],
1026 (m), 978 (m), 779 (m) cm–1. MS (FAB): m/z (%) = 203 [M +
Na]+, 181 (100) [M + H]+, 179, 164, 150, 124, 108, 93. HRMS
(C9H12NaN2O2): calcd. 203.0796; found 203.0804.
5
Ar), 127.7 (+, C-2Ј,6ЈAr), 128.0 (+, C-4ЈAr), 128.3 (+, C-3Ј,5ЈAr),
Benzyl [2-(Pyridin-3-yl)-1,3-dioxan-5-yl]carbamate (4b-Cbz): Pre-
pared by GP A; yield up to 56% (793 mg). cis/trans = 10:1.
135.6 (Cquat, C-1ЈAr), 136.6 (+, C-4Ar), 149.4 (+, C-6Ar), 154.3
(Cquat, C-2Ar), 157.6 (Cquat, C=O) ppm. IR (neat): ν = 3435 [w,
˜
ν(OH)], 3064 [w, νAr(C–H)], 2952 [w, ν(CH2)], 2891 [w, ν(CH2)],
1708 [m, ν(C=O)], 1592 [w, νAr(C=C)], 1498 (w), 1414 (m), 1357
(m), 1304 (w), 1126 [w, ν(C–O)], 1080 [w, ν(C–O)], 1049 [w, ν(C–
O)], 995 (w), 771 (w), 749 (w), 698 (w), 613 (w) cm–1. MS (FAB):
m/z (%) = 337 [M + Na]+, 315 (100) [M + H]+, 271, 207, 179, 108,
91 [C7H7]+. HRMS (C17H19N2O4): calcd. 315.1345; found
315.1343.
cis-4b-Cbz: Rf
= 0.56 (CH2Cl2/MeOH =
10:1). 1H NMR
3
(400 MHz, CDCl3): δ = 3.77 (d, J = 8.8 Hz, 1 H, 5-H), 4.6 (mc, 4
H, 4,6-H), 5.12 (s, 2 H, CH2Ph), 5.59 (s, 1 H, 2-H), 5.89 (mc, 1 H,
NH), 7.26–7.38 (m, 6 H, 5,2Ј–6Ј-HAr), 7.78 (d, J = 7.9 Hz, 1 H,
4-HAr), 8.59 (d, J = 4.7 Hz, 1 H, 6-HAr), 8.69 (d, J = 1.2 Hz, 1
H, 2-HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 45.4 (+, C-5),
66.9 (–, CH2Ph), 70.7 (–, C-4,6), 99.8 (+, C-2), 123.1 (+, C-5Ar),
128.1 (+, C-3Ј,5ЈAr), 128.2 (+, C-4ЈAr), 128.5 (+, C-2Ј,6ЈAr), 133.3
(Cquat, C-3Ar), 133.5 (+, C-4Ar), 136.2 (Cquat, C-1ЈAr), 147.8 (+, C-
3
3
4
2-[3-(Benzyloxycarbonyl)-4-(hydroxymethyl)oxazolidin-2-yl]pyridine
1-Oxide (8aЈ-Cbz): Prepared by slightly modified GP A, NBS used
as the catalyst in acetonitrile; yield 4% (31.9 mg). Rf = 0.14
2Ar), 150.2 (+, C-6Ar), 155.8 (Cquat, C=O) ppm. IR (DRIFT): ν =
˜
1
3260 [m, ν(OH)], 3036 [m, νAr(C–H)], 2975 [m, ν(CH2)], 2943 [m,
ν(CH2)], 2883 [m, ν(CH2)], 1718 [s, ν(C=O)], 1535 [m, νAr(C=C)],
1304 (m), 1275 (m), 1232 (m), 1172 [m, ν(C–O)], 1101 [m, ν(C–O)],
1072 [m, ν(C–O)], 1001 (s), 979 (m), 715 (m) cm–1. MS (FAB): m/z
(%) = 315 (100) [M + H]+, 261, 217, 173, 120, 107 [C7H7O]+, 91
[C7H7]+. HRMS (C17H19N2O4): calcd. 315.1345; found 315.1348.
(CH2Cl2/MeOH = 20:1). H NMR (400 MHz, CDCl3): δ = 3.70–
3.92 (m, 3 H, CH2), 4.13 (mc, 1 H, 4-H), 4.56 (mc, 2 H, CH2, 2-
H), 5.09 (s, 2 H, CH2Ph), 5.87 (d, 3J = 8.3 Hz, 1 H, NH), 7.27–
7.35 (m, 5 H, 2Ј–6Ј-HAr), 7.49 (ddd, 4J = 1.2, 3J = 4.8, 3J = 7.7 Hz,
1 H, 5-HAr), 7.85 (ddd, 4J = 1.7, 3J = 7.7, 3J = 7.7 Hz, 1 H, 4-
3
5
4
HAr), 8.11 (d, J = 7.7 Hz, 1 H, 3-HAr), 8.70 (ddd, J = 0.8, J =
1.7, J = 4.8 Hz, 1 H, 6-HAr) ppm. 13C NMR (100 MHz, CDCl3):
3
trans-4b-Cbz: Rf = 0.51 (CH2Cl2/MeOH = 10:1). 1H NMR
(500 MHz, CDCl3): δ = 3.60 (t, 2J = 10.4 Hz, 2 H, 4,6-H), 4.08
δ = 51.3 (+, C-4), 62.0 (–, CH2OH), 65.5 (–, C-5), 66.9 (CH2Ph),
77.2 (+, C-2), 125.4 (+, C-3Ar), 127.3 (+, C-4Ar), 128.1 (+, C-
2Ј,6ЈAr), 128.1 (+, C-4ЈAr), 128.5 (+, C-3Ј,5ЈAr), 137.3 (+, C-5Ar),
147.3 (Cquat, C-1ЈAr), 149.7 (+, C-6Ar), 156.2 (Cquat, C-2Ar), 165.0
3
2
(mc, 1 H, 5-H), 4.36 (dd, J = 4.2, J = 10.4 Hz, 2 H, 4,6-H), 4.83
3
(d, J = 7.9 Hz, 1 H, NH), 5.11 (s, 2 H, CH2Ph), 5.46 (s, 1 H, 2-
3
H), 7.28–7.39 (m, 6 H, 5,2Ј–6Ј-HAr), 7.81 (d, J = 7.6 Hz, 1 H, 4-
(Cquat, C=O) ppm. IR (DRIFT): ν = 3223 [m, ν(OH)], 3056 [m,
˜
3
HAr), 8.60 (d, J = 4.2 Hz, 1 H, 6-HAr), 8.69 (s, 1 H, 2-HAr) ppm.
νAr(C–H)], 2882 [m, ν(CH2)], 2803 (m), 2632 (w), 2007 (w), 1976
(w), 1729 [m, ν(C=O)], 1711 [m, νAr(C=C)], 1562 [m, νAr(C=C)],
1470 (m), 1448 (m), 1250 (m), 1213 (m), 1168 [m, ν(C–O)], 1057
(m), 930 (m), 918 (m), 760 (m), 738 (m), 705 (m) cm–1. MS (FAB):
m/z (%) = 353 [M + Na]+, 331 (100) [M + H]+, 243, 136, 108, 91
[C7H7]+. HRMS (C17H19N2O5): calcd. 331.1294; found 331.1292.
13C NMR (125 MHz, CDCl3): δ = 43.6 (+, C-5), 67.1 (–, CH2Ph),
69.7 (–, C-4,6), 99.1 (+, C-2), 123.3 (+, C-5Ar), 128.2 (+, C-3Ј,5ЈAr),
128.3 (+, C-4ЈAr), 128.6 (+, C-2Ј,6ЈAr), 133.1 (Cquat, C-3Ar), 134.0
(+, C-4Ar), 136.0 (Cquat, C-1ЈAr), 147.9 (+, C-2Ar), 150.1 (+, C-6Ar),
155.5 (Cquat, C=O) ppm. IR (DRIFT): ν = 3307 [m, ν(OH)], 3051
˜
[w, νAr(C–H)], 2981 [w, ν(CH2)], 2958 [w, ν(CH2)], 2857 [w,
ν(CH2)], 1679 [m, ν(C=O)], 1537 [m, νAr(C=C)], 1392 (m), 1313
(m), 1250 (w), 1165 [m, ν(C–N)], 1129 [m, ν(C–O)], 1103 [m, ν(C–
O)], 1049 [m, ν(C–O)], 700 (m) cm–1. MS (FAB): m/z (%) = 315
2-(Pyridin-2-yl)-1,3-dioxan-5-amine (4a-H): Prepared by GP B;
yield 90% (76.8 mg). If a mixture of isomers was deprotected, the
cis/trans ratio was preserved.
3842
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3837–3846

Novel 2,5-Disubstituted 1,3-Dioxanes and Oxazolidines
(100) [M + H]+, 261, 217, 176, 124, 107 [C7H7O]+, 91 [C7H7]+.
HRMS (C17H19N2O4): calcd. 315.1345; found 315.1342.
C=O) ppm. IR (DRIFT): ν = 3305 [w, ν(NH )], [w, νAr(C–H)],
˜
2
2978 [w, ν(CH2)], 2879 [w, ν(CH2)], 1963 (w), 1768 (w), 1728 [w,
ν(C=O)], 1682 [w, νAr(C=C)], 1606 [w, νAr(C=C)], 1537 [w,
νAr(C=C)], 1454 (w), 1413 (w), 1279 (w), 1127 [w, ν(C–N)], 1047
[w, ν(C–O)], 983 (w), 851 (w), 812 (w), 756 (w), 700 (w), 631 (w),
591 (w), 558 (w), 493 (w), 478 (w) cm–1. MS (FAB): m/z (%) = 315
(100) [M + H]+, 215, 207 [M – C7H7O]+, 124, 108, 91 [C7H7]+.
HRMS (C17H19N2O4): calcd. 315.1345; found 315.1346.
2-(Pyridin-3-yl)-1,3-dioxan-5-amine (4b-H): Prepared by GP B;
yield quantitative (236 mg). If a mixture of isomers was depro-
tected, the cis/trans ratio was preserved.
cis-4b-H·HNO3: Rf = 0.06 (CH2Cl2/MeOH = 10:1). 1H NMR
2
(400 MHz, CD3OD): δ = 3.43 (mc, 1 H, 5-H), 4.25 (dd, J = 13.0,
3J = 1.1 Hz, 2 H, 4,6-H), 4.39 (dd, 2J = 13.0, 3J = 1.1 Hz, 2 H,
3
3
4-[3-(Benzyloxycarbonyl)-4-(hydroxymethyl)oxazolidin-2-yl]pyridine
4,6-H), 5.80 (s, 1 H, 2-H), 7.47 (dd, J = 5.0, J = 7.9 Hz, 5-HAr),
8.01 (mc, 1 H, 4-HAr), 8.54 (dd, 4J = 1.5, 3J = 5.0 Hz, 1 H, 6-
1-Oxide (8cЈ-Cbz): Prepared by GP A; yield up to 25% (345 mg).
1
Ar), 8.69 (d, 4J = 1.5 Hz, 1 H, 2-HAr) ppm. 13C NMR (100 MHz,
Rf = 0.43 (CH2Cl2/MeOH = 10:1). H NMR (500 MHz, CDCl3):
H
δ = 2.88 (s, 1 H, OH), 3.78 (mc, 2 H, CH2), 4.14 (s, 1 H, 4-H), 4.49
(mc, 2 H, CH2), 5.10 (mc, 2 H, CH2Ph), 5.40 (mc, 1 H, 2-H), 7.29–
CD3OD): δ = 47.0 (+, C-5), 69.2 (–, C-4,6), 101.3 (+, C-2), 125.0
(+, C-5Ar), 135.5 (Cquat, C-3Ar), 136.4 (+, C-4Ar), 148.4 (+, C-2Ar),
3
7.36 (m, 5 H, 2Ј–6Ј-HAr), 7.80 (d, J = 5.0 Hz, 2 H, 3,5-HAr), 8.75
150.6 (+, C-6Ar) ppm. IR (DRIFT): ν = 3009 (m), 1630 (m), 1602
˜
(d, 3J = 5.0 Hz, 2 H, 2,6-HAr) ppm. 13C NMR (125 MHz, CDCl3):
δ = 51.5 (+, C-4), 61.6 (–, CH2OH), 64.3 (–, C-5), 67.1 (–, CH2Ph),
100.0 (+, C-2), 122.9 (+, C-3,5Ar), 128.1 (+, C-2Ј,6ЈAr), 128.3 (+,
C-4ЈAr), 128.5 (+, C-3Ј,5ЈAr), 136.1 (Cquat, C-1ЈAr), 136.9 (Cquat, C-
[m, δ = (NH2)], 1523 [m, νAr(C=C)], 1386 (m), 1327 (m), 1186 [m,
ν(C–O)], 1157 [m, ν(C-O)], 1137 [m, ν(C–O)], 1070 [m, ν(C–O)],
1012 (m) 802 (m), 712 (m) cm–1. MS (FAB): m/z (%) = 181
(100) [M + H]+, 165, 137 [M – C2H5N]+, 115, 107, 102 [M –
C4H8NO2]+, 89. HRMS (C9H13N2O2): calcd. 181.0977; found
181.0979.
4), 150.5 (+, C-2,6Ar), 165.2 (Cquat, C=O) ppm. IR (DRIFT): ν =
˜
3306 [m, ν(OH)], 3069 [m, νAr(C–H)], 2943 [m, ν(CH2)], 2905 [m,
ν(CH2)], 1728 (m), 1694 [m, ν(C=O)], 1540 [m, νAr(C=C)], 1415
(m), 1333 (m), 1295 (m), 1252 (m), 1139 [m, ν(C–O)], 1092 [m, ν(C–
O)], 1029 [m, ν(C–O)], 687 (m) cm–1. MS (FAB): m/z (%) = 353 [M
+ Na]+, 331 (100) [M + H]+, 315 [M + H – O]+, 261, 241, 223 [M –
C7H7O]+, 214, 208, 165, 124, 107 [C7H7O]+, 91 [C7H7]+. HRMS
(C17H19N2O5): calcd. 331.1294; found 331.1292. C17H18N2O5
(330): calcd. C 61.81, H 5.49, N 8.48; found C 62.04, H 5.40, N
8.72.
trans-4b-H: Rf
(500 MHz, CD3OD): δ = 3.18 (mc, 1 H, 5-H), 3.64 (t, 2J = 11.0 Hz,
= 0.20 (CH2Cl2/MeOH =
10:1). 1H NMR
3
2
2 H, 4,6-H), 4.27 (dd, J = 4.8, J = 11.0 Hz, 2 H, 4,6-H), 5.56 (s,
1 H, 2-H), 7.44 (dd, 3J = 4.9, 3J = 7.9 Hz, 5-HAr), 7.91 (d, 3J =
3
7.9 Hz, 1 H, 4-HAr), 8.51 (d, J = 4.8 Hz, 1 H, 6-HAr), 8.60 (mc, 1
H, 2-HAr) ppm. 13C NMR (125 MHz, CD3OD): δ = 44.9 (+, C-5),
72.8 (–, C-4,6), 100.0 (+, C-2), 125.0 (+, C-5Ar), 135.9 (Cquat, C-
3
Ar), 136.3 (+, C-4Ar), 148.2 (+, C-2Ar), 150.3 (+, C-6Ar) ppm. MS
(FAB): m/z (%) = 181 (100) [M + H]+, 164 [M – NH2]+, 137 [M –
2-(Pyridin-4-yl)-1,3-dioxan-5-amine (4c-H): Prepared by GP B;
C2H5N]+, 124, 108, 91. HRMS (C9H13N2O2): calcd. 181.0977; yield 98% (37.6 mg). If a mixture of isomers was deprotected, the
found 181.0979.
cis/trans ratio was preserved.
1
Benzyl [2-(Pyridin-4-yl)-1,3-dioxan-5-yl]carbamate (4c-Cbz): Pre-
pared by GP A; yield up to 17% (242 mg). cis/trans = 1.4:1.
cis-4c-H: Rf = 0.03 (CH2Cl2/MeOH = 10:1). H NMR (400 MHz,
CD3OD): δ = 2.89 (mc, 1 H, 5-H), 4.06 (dd, 2J = 11.9, 3J = 1.3 Hz,
2 H, 4,6-H), 4.25 (mc, 2 H, 4,6-H), 5.64 (s, 1 H, 2-H), 7.55 (mc, 2
H, 3,5-HAr), 8.55 (mc, 2 H, 2,6-HAr) ppm. 13C NMR (100 MHz,
CD3OD): δ = 49.6 (+, C-5), 72.9 (–, C-4,6), 100.6 (+, C-2), 122.7
(+, C-3,5Ar), 149.1 (Cquat, C-4Ar), 150.1 (+, C-2,6Ar) ppm. IR
cis-4c-Cbz: Rf = 0.58 (CH2Cl2/MeOH = 10:1). 1H NMR (600 MHz,
3
CDCl3): δ = 3.78 (d, J = 8.8 Hz, 1 H, 5-H), 4.17 (mc, 4 H, 4,6-H),
3
5.12 (s, 2 H, CH2Ph), 5.53 (s, 1 H, 2-H), 5.81 (d, J = 8.8 Hz, 1 H,
NH), 7.30–7.37 (m, 5 H, 2Ј–6Ј-HAr), 7.38 (d, 3J = 5.8 Hz, 2 H, 3,5-
H
Ar), 8.63 (d, 3J = 5.8 Hz, 2 H, 2,6-HAr) ppm. 13C NMR
(DRIFT): ν = 3431 [m, ν(NH )], 2878 [m, ν(CH )], 2577 (w), 2116
˜
2
2
(vw), 1755 (vw), 1631 [w, νAr(C=C)], 1536 [w, νAr(C=C)], 1387 (m),
1276 (w), 1245 (w), 1157 [w, ν(C–N)], 1131 [w, ν(C–O)], 1095 [w,
ν(C–O)], 1068 [w, ν(C–O)], 1016 [w, ν(C–O)], 986 (w), 968 (w), 941
(w), 819 (w), 802 (w), 785 (w), 738 (w), 655 (w), 592 (w), 525 (w),
497 (w), 446 (w), 432 (w) cm–1. MS (EI): m/z (%) = 180 (2) [M]+,
163 (3), 123 (75) [C6H5NO2]+, 122 (84), 108 (49), 106 (11), 101 (5),
78 (8), 68 (4), 58 (32), 43 (100). HRMS (C9H13N2O2): calcd.
181.0977; found 181.0975.
(125 MHz, CDCl3): δ = 45.4 (+, C-5), 67.0 (–, CH2Ph), 70.8 (–, C-
4,6), 99.5 (+, C-2), 120.7 (+, C-3,5Ar), 128.1 (+, C-3Ј,5ЈAr), 128.2
(+, C-4ЈAr), 128.5 (+, C-2Ј,6ЈAr), 136.2 (Cquat, C-1ЈAr), 146.0 (Cquat
,
C-4Ar), 149.7 (+, C-2,6Ar), 155.8 (Cquat, C=O) ppm. IR (DRIFT):
ν = 3205 [m, ν(OH)], 3035 [m, νAr(C–H)], 2950 [w, ν(CH2)], 2882
˜
[w, ν(CH2)], 1955 (vw), 1716 [m, ν(C=O)], 1610 [m, νAr(C=C)],
1552 [m, νAr(C=C)], 1468 (w), 1418 (w), 1403 (w), 1345 (w), 1329
(w), 1302 (m), 1284 (m), 1250 (m), 1176 [m, ν(C–N)], 1113 [m, ν(C–
O)], 1088 [m, ν(C–O)], 1070 [m, ν(C–O)], 1027 [m, ν(C–O)], 1009
(m), 988 (m), 947 (w), 917 (w), 859 (w), 842 (w), 817 (w), 753 (m),
721 (m), 698 (m), 657 (w), 598 (w), 578 (w), 553 (w), 539 (w), 519
(w) cm–1. MS (FAB): m/z (%) = 315 (100) [M + H]+, 270, 223, 207
[M – C7H7O]+, 124, 108, 91 [C7H7]+. HRMS (C17H19N2O4): calcd.
315.1345; found 315.1342.
trans-4c-H: Rf
(250 MHz, CD3OD): δ = 3.05 (mc, 1 H, 5-H), 3.55 (mc, 2 H, 4,6-
= 0.11 (CH2Cl2/MeOH =
10:1). 1H NMR
2
3
H), 4.24 (dd, J = 11.3, J = 4.9 Hz, 2 H, 4,6-H), 5.46 (s, 1 H, 2-
3
3
H), 7.50 (d, J = 5.9 Hz, 2 H, 3,5-HAr), 8.54 (d, J = 5.9 Hz, 2 H,
2,6-HAr) ppm. 13C NMR (100 MHz, CD3OD): δ = 52.8 (+, C-5),
71.9 (–, C-4,6), 100.3 (+, C-2), 122.8 (+, C-3,5Ar), 149.1 (Cquat, C-
trans-4c-Cbz: Rf = 0.53 (CH2Cl2/MeOH = 10:1). 1H NMR
4Ar), 150.2 (+, C-2,6Ar) ppm. IR (DRIFT): ν = 3348 (w), 3288 [w,
˜
(600 MHz, CDCl3): δ = 3.61 (t, 2J = 10.2 Hz, 2 H, 4,6-H), 4.05 ν(NH2)], 3037 [w, νAr(C–H)], 2978 (w), 2929 [w, ν(CH2)], 2851 [w,
3
2
(mc, 1 H, 5-H), 4.35 (dd, J = 5.1, J = 10.2 Hz, 2 H, 4,6-H), 4.80
ν(CH2)], 2771 (vw), 1948 (vw), 1875 (vw), 1755 (w), 1693 [w,
νAr(C=C)], 1605 [w, νAr(C=C)], 1565 [w, νAr(C=C)], 1462 (w), 1416
(w), 1393 (w), 1327 (w), 1288 (w), 1234 (w), 1138 [w, ν(C–N)], 1094
3
(d, J = 7.0 Hz, 1 H, NH), 5.10 (s, 2 H, CH2Ph), 5.41 (s, 1 H, 2-
H), 7.31–7.42 (m, 7 H, 3,5,2Ј–6Ј-HAr), 8.64 (s, 2 H, 2,6-HAr) ppm.
13C NMR (125 MHz, CDCl3): δ = 43.6 (+, C-5), 67.2 (-, CH2Ph), [w, ν(C–O)], 1067 [w, ν(C–O)], 1030 [w, ν(C–O)], 993 (w), 931 (w),
69.6 (–, C-4,6), 98.9 (+, C-2), 121.0 (+, C-3,5Ar), 128.2 (+, C- 868 (w), 806 (w), 739 (w), 676 (w), 644 (w), 566 (w), 519 (vw), 480
3Ј,5ЈAr), 128.3 (+, C-4ЈAr), 128.6 (+, C-2Ј,6ЈAr), 136.0 (Cquat, C-
1ЈAr), 145.6 (Cquat, C-4Ar), 149.9 (+, C-2,6Ar), 155.5 (Cquat
(vw), 409 (vw) cm–1. MS (EI): m/z (%) = 180 (2) [M]+, 163 (2), 153
,
(6), 136 (3), 123 (98) [C6H5NO2]+, 122 (100), 108 (61), 106 (15), 89
Eur. J. Org. Chem. 2010, 3837–3846
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3843

A. J. Rüger, M. Nieger, M. Es-Sayed, S. Bräse
(7) [C3H7NO2]+, 78 (10), 58 (6), 43 (80). HRMS (C9H13N2O2): 2-(Furan-2-yl)-1,3-dioxan-5-amine (4e-H): Prepared by GP B; yield
FULL PAPER
calcd. 181.0977; found 181.0979.
91% (136 mg). If a mixture of isomers was deprotected, the
cis/trans ratio was preserved.
Benzyl
4-(Hydroxymethyl)-2-(1H-pyrrol-2-yl)oxazolidine-3-carb-
trans-4e-H: Rf
(400 MHz, CD3OD): δ = 3.11 (tt, 3J = 4.7, 3J = 9.9 Hz, 1 H, 5-H),
= 0.40 (CH2Cl2/MeOH =
10:1). 1H NMR
oxylate (8d-Cbz): Prepared by GP A; yield up to 4% (27.2 mg). Rf
= 0.58 (CH2Cl2/MeOH = 10:1). H NMR (250 MHz, CDCl3): δ =
1
2
3
2
3.56 (dd, J = 11.5, J = 9.9 Hz, 2 H, 4,6-H), 4.20 (dd, J = 11.5,
2.37 (br. s, 1 H, OH), 3.70 (mc, 2 H, CH2), 3.98 (mc, 1 H, 4-H),
4.27 (mc, 2 H, CH2), 5.08 (s, 2 H, CH2Ph), 5.40 (mc, 1 H, 2-H),
7.28–7.37 (m, 7 H, 3,4,2Ј–6Ј-HAr), 8.04 (mc, 1 H, 5-HAr) ppm. 13C
NMR (100 MHz, CDCl3): δ = 51.3 (+, C-4), 61.5 (–, CH2OH),
62.4 (–, C-5), 67.0 (–, CH2Ph), 77.2 (C-2), 128.1 (+, C-4,2Ј,6ЈAr),
128.2 (+, C-4ЈAr), 128.5 (+, C-2,3Ј,5ЈAr, Cquat), 136.0 (Cquat, C-1ЈAr),
156.2 (Cquat, C=O), 160.9 (+, C-3,5Ar) ppm. MS (FAB): m/z (%) =
270, 254, 226, 217, 182, 176, 132, 107, 91, 77, 69, 57, 43. Due to
strong fragmentation, the protonated molecular ion was not ob-
served by FAB-MS.
3J = 4.7 Hz, 2 H, 4,6-H), 5.52 (s, 1 H, 2-H), 6.40 (dd, J = 3.2, J
3
3
4
3
= 1.7 Hz, 4-HAr), 6.43 (mc, 1 H, 3-HAr), 7.48 (dd, J = 0.8, J =
1.7 Hz, 1 H, 5-HAr) ppm. 13C NMR (100 MHz, CD3OD): δ = 45.2
(+, C-5), 72.3 (–, C-4,6), 96.7 (+, C-2), 108.7 (+, C-3Ar), 111.2 (+,
C-4Ar), 143.8 (+, C-5Ar), 152.0 (Cquat, C-2Ar) ppm. IR (DRIFT): ν
˜
= 3348 [w, ν(NH2)], 2854 [w, ν(CH2)], 1709 (w), 1658 [w, νAr(C=C)],
1547 [w, νAr(C=C)], 1368 (w), 1233 [w, ν(C–N)], 1080 [w, ν(C–O)],
883 (w), 823 (vw), 748 (vw), 600 (vw), 492 (vw) cm–1. MS (FAB):
m/z (%) = 170 (100) [M + H]+, 158, 149, 132, 116, 107, 102
[C4H8NO2]+, 97, 95, 91. HRMS (C8H11NO3): calcd. 170.0817;
found 170.0814.
Benzyl [2-(Furan-2-yl)-1,3-dioxan-5-yl]carbamate (4e-Cbz): Pre-
pared by GP A; yield up to 33% (222 mg). Mixture of isomers:
cis/trans = 2.6:1. Rf = 0.75/0.69 (CH2Cl2/MeOH = 10:1). 1H NMR
(400 MHz, CDCl3): δ = 3.58 (mc, 2 H, 4t,6t-H), 3.74 (mc, 1 H, 5c-
H), 3.99–4.15 (m, 5 H, 5t,4c,6c-H), 4.31 (dd, 3J = 5.0, 2J = 11.1 Hz,
2 H, 4t,6t-H), 4.88 (mc, 1 H, NHt), 5.10 (s, 2 H, CH2Pht), 5.12 (s,
cis-4e-H·HNO3: Rf = 0.18 (CH2Cl2/MeOH = 10:1). 1H NMR
(400 MHz, CD3OD): δ = 3.40 (mc, 1 H, 5-H), 4.19 (mc, 2 H, 4,6-
H), 4.32 (mc, 2 H, 4,6-H), 5.73 (s, 1 H, 2-H), 6.42 (dd, J = 3.3, J
= 1.8 Hz, 4-HAr), 6.54 (mc, 1 H, 3-HAr), 7.50 (dd, J = 0.8, J =
1.8 Hz, 1 H, 5-HAr) ppm. 13C NMR (100 MHz, CD3OD): δ = 47.0
(+, C-5), 68.8 (–, C-4,6), 97.8 (+, C-2), 109.1 (+, C-3Ar), 111.3 (+,
3
3
4
3
2 H, CH2Phc), 5.53 (s, 1 H, 2t-H), 5.61 (s, 1 H, 2c-H), 5.89 (d, J
3
= 8.7 Hz, 1 H, NHc), 6.37 (dd, 3J = 1.8, 3J = 3.3 Hz, 1 H, 4c,t
-
-
C-4Ar), 143.9 (+, C-5Ar), 151.6 (Cquat, C-2Ar) ppm. IR (DRIFT): ν
HAr), 6.45 (d, J = 3.3 Hz, 3c,t-HAr), 7.30–7.39 (m, 5 H, 2Јc,t–6Јc,t
3
˜
= 3439 [w, ν(NH2)], 1640 [w, νAr(C=C)], 1534 [w, νAr(C=C)], 1356
(w), 1156 [vw, ν(C–N)], 1115 [vw, ν(C–O)], 1042 [w, ν(C–O)], 968
(vw), 931 (vw), 883 (vw), 823 (vw), 741 (vw) cm–1. MS (FAB): m/z
(%) = 233 [M + H + HNO3]+, 217, 189, 170 [M + H]+, 149, 145,
HAr), 7.41 (dd, 4J = 0.9, 3J = 1.8 Hz, 1 H, 5c,t-HAr) ppm. 13C NMR
(100 MHz, CDCl3): δ = 43.7 (+, C-5t), 45.5 (+, C-5c), 63.5 (–,
CH2Pht), 66.9 (–, CH2Phc), 69.0 (–, C-4t,6t), 70.6 (–, C-4c,6c), 95.2
(+, C-2t), 96.3 (+, C-2c), 107.7 (+, C-3cAr), 108.1 (+, C-3tAr), 110.2
(+, C-4cAr), 110.3 (+, C-4tAr), 128.1 (+, C-3Ј,5ЈcAr), 128.1 (+, C-
4ЈcAr), 128.2 (+, C-3Ј,5ЈtAr), 128.3 (+, C-4ЈtAr), 128.5 (+, C-2Ј,6ЈcAr),
128.5 (+, C-2Ј,6ЈtAr), 136.0 (Cquat, C-1ЈtAr), 136.2 (Cquat, C-1ЈcAr),
142.7 (+, C-5cAr), 142.7 (+, C-5tAr), 149.8 (Cquat, C-2tAr), 150.1
(Cquat, C-2cAr), 155.5 (Cquat, C=Ot), 155.9 (Cquat, C=Oc) ppm. IR
133 (100), 115, 101. HRMS (C8H13NO3+NO3 ): calcd. 233.0774;
–
found 233.0776.
Benzyl [2-(Furan-3-yl)-1,3-dioxan-5-yl]carbamate (4f-Cbz): Pre-
pared by GP A; yield up to 63% (423 mg). Mixture of isomers:
1
cis/trans = 8:1. Rf = 0.48/0.41 (CH2Cl2/MeOH = 20:1). H NMR
(400 MHz, CDCl3): δ = 3.53 (dd, 3J = 10.3, 2J = 10.5 Hz, 2 H,
4t,6t-H), 3.72 (mc, 1 H, 5c-H), 3.98–4.12 (m, 5 H, 5t,4c,6c-H), 4.30
(dd, 3J = 4.5, 2J = 10.5 Hz, 2 H, 4t,6t-H), 4.69 (mc, 1 H, NHt), 5.10
(DRIFT): ν = 3323 [m, ν(OH)], 3121 [w, νAr(C–H)], 2947 [m,
˜
ν(CH2)], 2865 [m, ν(CH2)], 1717 [m, ν(C=O)], 1508 [m, νAr(C=C)],
1307 (s), 1234 (m), 1175 [m, ν(C–O)], 1154 [m, ν(C–O)], 1108 [m,
ν(C–O)], 1075 [m, ν(C–O)], 976 (m), 749 (m) cm–1. MS (FAB):
m/z (%) = 326 [M + Na]+, 304 [M + H]+, 261, 236, 208 [M –
C5H4O2]+, 165, 123, 107 [C7H7O]+, 97, 91 (100) [C7H7]+. HRMS
(C16H18NO5): calcd. 304.1185; found 304.1182. C16H17NO5 (303):
calcd. C 63.36, H 5.65, N 4.62; found C 62.84, H 5.63, N 4.36.
(s, 2 H, CH2Pht), 5.12 (s, 2 H, CH2Phc), 5.46 (s, 1 H, 2t-H), 5.56
3
(s, 1 H, 2c-H), 5.83 (d, J = 8.6 Hz, 1 H, NHc), 6.45 (mc, 1 H, 4c,t
-
-
HAr), 7.31–7.40 (m, 6 H, 5c,t,2Јc,t–6Јc,t-HAr), 7.51 (mc, 1 H, 2c,t
H
Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 43.7 (+, C-5t), 45.5
(+, C-5c), 66.9 (–, CH2Phc), 67.1 (–, CH2Pht), 69.3 (–, C-4t,6t), 70.5
(–, C-4c,6c), 96.4 (+, C-2t), 97.4 (+, C-2c), 108.0 (+, C-4cAr), 108.3
(+, C-4tAr), 123.4 (Cquat, C-3tAr), 123.9 (Cquat, C-3cAr), 128.2 (+, C-
3Ј,5ЈcAr), 128.2 (+, C-4ЈcAr), 128.3 (+, C-3Ј,5ЈtAr), 128.4 (+, C-4ЈtAr),
128.6 (+, C-2Ј,6ЈcAr), 128.6 (+, C-2Ј,6ЈtAr), 136.0 (Cquat, C-1ЈtAr),
136.3 (Cquat, C-1ЈcAr), 140.4 (+, C-2cAr), 140.5 (+, C-2tAr), 143.3
Benzyl 2-(Furan-2-yl)-4-(hydroxymethyl)oxazolidine-3-carboxylate
(8e-Cbz): Prepared by GP A; yield up to 21% (141 mg). Mixture of
1
isomers: a/b = 1:3.4. Rf = 0.56 (CH2Cl2/MeOH = 10:1). H NMR
(400 MHz, CDCl3): δ = 3.57–4.33 (m, 6 H, 4a,b-H, 2 CH2a,b, OHb),
5.09–5.16 (m, 2 H, CH2Pha,b), 5.90 (d, 3J = 8.7 Hz, 1 H, OHa),
(+, C-5cAr), 143.3 (+, C-5tAr), 155.5 (Cquat, C=Ot), 155.9 (Cquat
,
6.13 (s, 1 H, 2a-H), 6.15 (s, 1 H, 2b-H), 6.26–6.46 (m, 2 H, 3a,b,4a,b
-
C=Oc) ppm. IR (DRIFT): ν = 3278 [s, ν(OH)], 3146 [m, νAr(C–
˜
H), 7.06 (mc, 1 H, 5a-HAr), 7.12 (mc, 1 H, 5b-HAr), 7.26–7.42 (m,
5 H, 2Јa,b–6Јa,b-HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 45.5
H)], 2964 [m, ν(CH2)], 2868 [m, ν(CH2)], 1703 [s, ν(C=O)], 1505
[m, νAr(C=C)], 1459 (s), 1409 (s), 1344 [s, ν(C–N)], 1237 (m), 1154
[s, ν(C–O)], 1117 [s, ν(C–O)], 1089 [s, ν(C–O)], 1064 [s, ν(C–O)],
996 (s), 939 (s), 877 (m), 804 (s), 744 (m), 699 (s) cm–1. MS (FAB):
m/z (%) = 304 [M + H]+, 255, 217, 208 [M – C5H4O2]+, 173, 123,
107 [C7H7O]+, 97 (100), 91 [C7H7]+. HRMS (C16H18NO5): calcd.
304.1185; found 304.1182. C16H17NO5 (303): calcd. C 63.36, H
5.65, N 4.62; found C 63.07, H 5.63, N 4.49.
(+, C-5a), 59.2 (+, C-5b), 64.0 (–, CH2b), 66.9 (–, CH2 ), 67.5 (–,
a
a
a
CH2 ), 67.7 (–, CH2b), 68.0 (–, CH2b), 70.6 (–, CH2 ), 83.3 (+, C-
2a), 83.8 (+, C-2b), 107.7 (+, C-3aAr), 108.7 (+, C-4aAr), 109.4 (+,
C-3bAr), 110.3 (+, C-4bAr), 127.7–128.6 (+, m, 5 CHa,bAr), 135.7
(Cquat, C-1ЈbAr), 136.2 (Cquat, C-1ЈaAr), 142.6 (+, C-5aAr), 143.0 (+,
C-5bAr), 150.1 (Cquat, C-2aAr), 151.0 (Cquat, C-2bAr), 155.9 (Cquat
,
C=Oa,b) ppm. IR (neat): ν = 3440 [w, ν(OH)], 3034 [w, νAr(C–H)],
˜
2953 [w, ν(CH2)], 2887 [w, ν(CH2)], 1707 [s, ν(C=O)], 1499 [w,
Benzyl 2-(Furan-3-yl)-4-(hydroxymethyl)oxazolidine-3-carboxylate
νAr(C=C)], 1416 (s), 1357 (m), 1184 [w, ν(C–O)], 1127 [m, ν(C–O)], (8f-Cbz): Prepared by GP A; yield up to 9% (57.9 mg). Mixture of
1073 [m, ν(C–O)], 743 (m) cm–1. MS (FAB): m/z (%) = 326 [M + isomers: a/b = 1:4. Rf = 0.47 (CH2Cl2/MeOH = 10:1). 1H NMR
Na]+, 304 [M + H]+, 260, 236, 208 [M – C5H4O2]+, 196, 168, 107 (250 MHz, CDCl3): δ = 3.62–3.78 (m, 2 H, CH2a,b), 3.84–3.99 (m,
[C7H7O]+, 102, 91 (100) [C7H7]+. HRMS (C16H18NO5): calcd.
304.1185; found 304.1189.
1 H, 4a,b-H), 4.07–4.25 (m, 2 H, CH2a,b), 5.03–5.20 (m, 2 H,
CH2Pha,b), 6.15 (s, 1 H, 2b-H), 6.18 (s, 1 H, 2a-H), 6.34 (s, 1 H, 4a-
3844
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3837–3846

Novel 2,5-Disubstituted 1,3-Dioxanes and Oxazolidines
HAr), 6.40 (s, 4b-HAr), 7.11–7.51 (m, 7 H, 2a,b,5a,b,2Јa,b–6Јa,b
-
Benzyl 2-(Thiophen-2-yl)-4-(hydroxymethyl)oxazolidine-3-carboxyl-
ate (8g-Cbz): Prepared by GP A; yield up to 21% (149 mg). Decom-
position occurred after a short time. Mixture of isomers: a/b =
HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 45.5 (+, C-5b), 53.3
(+, C-5a), 63.3 (–, CH2 ), 66.9 (–, CH2b), 67.5 (–, CH2 ), 67.8 (–,
a
a
CH2a,b), 70.4 (–, CH2a,b), 84.5 (+, C-2a), 97.3 (+, C-2b), 108.0 (+, 1:7.5. Rf = 0.27 (CH2Cl2/MeOH = 20:1). 1H NMR (250 MHz,
C-4aAr), 108.6 (+, C-4aAr), 123.9 (Cquat, C-3aAr), 124.7 (Cquat, C- CDCl3): δ = 3.61–4.26 (m, 5 H, 4a,b-H, 2 CH2a,b), 4.93–5.16 (m, 2
3bAr), 128.0–128.5 (+, m, 5 C, CHa,bAr), 135.6 (Cquat, C-1ЈbAr),
H, CH2Pha,b), 6.33 (s, 1 H, 2b-H), 6.35 (s, 1 H, 2a-H), 6.87–7.38
136.2 (Cquat, C-1ЈaAr), 140.3 (+, C-2aAr), 141.0 (+, C-2bAr), 143.2 (m, 8 H, 3a,b–5a,b,2Јa,b–6Јa,b-HAr) ppm. MS (FAB): m/z (%) = 342
(+, C-5bAr), 143.5 (+, C-5aAr), 151.3 (Cquat, C=Oa), 155.9 (Cquat
,
[M + Na]+, 320 [M + H]+, 276, 236, 212, 208, 184, 113, 102, 91
(100) [C7H7]+.
C=Ob) ppm. IR (neat): ν = 3434 [s, ν(OH)], 3065 [w νAr(C–H)],
˜
3034 (w), 2952 [m, ν(CH2)], 2884 [m, ν(CH2)], 1705 [s, ν(C=O)],
1603 [w, νAr(C=C)], 1501 [m, νAr(C=C)], 1419 (s), 1354 (s), 1306
(m), 1159 [m, ν(C–N)], 1127 [s, ν(C–O)], 1070 [s, ν(C–O)], 1020 [s,
ν(C–O)], 978 (m), 875 (m), 777 (m), 699 (m), 602 (m) cm–1. MS
(FAB): m/z (%) = 304 [M + H]+, 260, 236, 217, 208, 107
[C7H7O]+, 102, 91 (100) [C7H7]+, 69, 57, 43. HRMS (C16H18NO5):
calcd. 304.1185; found 304.1188.
Acknowledgments
We acknowledge Bayer CropScience for funding.
[1] World Health Organisation: http://www.who.int/mediacentre/
factsheets/fs310/en/index.html (accessed November 20th,
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2-(Furan-3-yl)-1,3-dioxan-5-amine (4f-H): Prepared by GP B; yield
72% (41.8 mg). The cis/trans ratio switched from 8:1 to 5.5:1 during
the reaction.
trans-4f-H: Rf
= 0.21 (CH2Cl2/MeOH =
20:1). 1H NMR
3
3
(400 MHz, CD3OD): δ = 3.01 (tt, J = 4.9, J = 10.2 Hz, 1 H, 5-
H), 3.47 (mc, 2 H, 4,6-H), 4.15 (ddd, 2J = 10.0, 3J = 4.9, 4J =
1.4 Hz, 2 H, 4,6-H), 5.44 (s, 1 H, 2-H), 6.44 (dd, 3J = 1.8, 3J =
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0.7 Hz, 4-HAr), 7.44 (t, J = 1.7 Hz, 1 H, 5-HAr), 7.53 (mc, 1 H, 2-
Nursing
News,
http://www.oncologynursingnews.com/
HAr) ppm. 13C NMR (100 MHz, CD3OD): δ = 45.2 (+, C-5), 73.7
(–, C-4,6), 97.8 (+, C-2), 109.6 (+, C-4Ar), 125.7 (Cquat, C-3Ar),
celecoxib-for-chemoprevention-in-lung-cancer/article/128126/
(accessed November 20, 2009).
141.7 (+, C-2Ar), 144.3 (+, C-5Ar) ppm. IR (neat): ν = 3344 [w,
˜
[6] European Medicines Agency, Doc.Ref.: EMEA/COMP/264/04.
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ν(NH2)], 3142 [w, ν(NH2)], 2925 [w, ν(CH2)], 2853 [w, ν(CH2)],
2306 (vw), 1709 (w), 1657 [m, νAr(C=C)], 1607 [m, νAr(C=C)], 1502
(w), 1461 (w), 1409 (w), 1381 (w), 1287 (w), 1230 (w), 1201 [w, ν(C–
N)], 1157 [w, ν(C–O)], 1097 [w, ν(C–O)], 1068 [w, ν(C–O)], 1021 [w,
ν(C–O)], 875 (w), 793 (w), 744 (vw), 655 (vw), 602 (vw) cm–1. MS
(FAB): m/z (%) = 170 (100) [M + H]+, 168, 149, 168, 111
[C6H7O2]+, 97, 95, 85. HRMS (C8H12NO3): calcd. 170.0817; found
170.0820.
1
cis-4f-H: Rf = 0.07 (CH2Cl2/MeOH = 20:1). H NMR (400 MHz,
CD3OD): δ = 2.76 (mc, 1 H, 5-H), 3.94 (mc, 2 H, 4,6-H), 4.12 (ddd,
3
4
2J = 12.1, J = 3.2, J = 1.4 Hz, 2 H, 4,6-H), 5.58 (s, 1 H, 2-H),
3
3
3
6.51 (dd, J = 1.8, J = 0.6 Hz, 4-HAr), 7.46 (t, J = 1.7 Hz, 1 H,
5-HAr), 7.57 (mc, 1 H, 2-HAr) ppm. 13C NMR (100 MHz, CD3OD):
δ = 46.7 (+, C-5), 72.7 (–, C-4,6), 98.5 (+, C-2), 109.5 (+, C-4Ar),
126.0 (Cquat, C-3Ar), 141.7 (+, C-2Ar), 144.3 (+, C-5Ar) ppm. IR
(neat): ν = 3362 [m, ν(NH )], 3148 [w, νAr(C–H)], 2858 [w, ν(CH2)],
˜
2
1709 (w), 1610 [w, νAr(C=C)], 1547 [w, νAr(C=C)], 1502 (w), 1450
(w), 1366 (m), 1280 (w), 1233 [w, ν(C–N)], 1150 [w, ν(C–O)], 1059
[w, ν(C–O)], 876 (w), 805 (w), 739 (w), 634 (w), 602 (w), 520
(vw) cm–1. MS (EI): m/z (%) = 169 (7) [M]+, 152 (5), 139 (2), 111
(20), 95 (12), 81 (4), 58 (20), 43 (100). HRMS (C8H11NO3): calcd.
169.0739; found 169.0738.
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3
(mc, 2 H, 4t,6t-H), 3.75 (d, J = 8.7 Hz, 1 H, 5c-H), 3.99–4.16 (m,
5 H, 5t,4c,6c-H), 4.34 (dd, 3J = 4.4, 2J = 10.9 Hz, 2 H, 4t,6t-H),
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7.41 (m, 6 H, 3c,t,2Јc,t–6Јc,t-HAr) ppm. MS (FAB): m/z (%) = 342
[M + Na]+, 320 [M + H]+, 236, 208, 165, 137, 113, 97, 91 (100)
[C7H7]+.
Eur. J. Org. Chem. 2010, 3837–3846
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3837–3846