Efficient synthesis of 2- and 3-substituted-2,3-dihydro [1,4]dioxino[2,3-b]pyridine derivatives

Article abstract of DOI:10.1016/j.tet.2004.06.041

A versatile new approach for the synthesis in three steps of 2-substituted-2,3-dihydro[1,4]dioxino[2,3-b]pyridines B via a Smiles rearrangement using easily available reagents is described. A study illustrating the influence of experimental conditions on the progress of the reaction is reported.

Full text of DOI:10.1016/j.tet.2004.06.041

Tetrahedron 60 (2004) 6461–6473
Efficient synthesis of 2- and 3-substituted-2,3-dihydro
[1,4]dioxino[2,3-b]pyridine derivatives
S. Lazar,a M. Soukri,a,b J. M. Leger,c C. Jarry,c M. Akssira,a R. Chirita,d I. C. Grig-Alexa,b,d
A. Finarud and G. Guillaumetb
,
*
a
´
´
´
Laboratoire de Chimie Bioorganique et Analytique, Universite Hassan II - Mohammedia, BP 146, 20800 Mohammedia, Morocco
Institut de Chimie Organique et Analytique, UMR CNRS 6005, Universite d’Orleans, BP 6759, 45067 Orleans Cedex 2, France
b
´
´
´
c
´
´
EA 2962, Pharmacochimie, Universite Victor Segalen Bordeaux II, 146, rue Leo Saignat, 33076 Bordeaux Cedex, France
` ´
Laboratoire de Synthese Organique et Analyse Structurale, Universite de Bacau, 157, rue de Marasesti, 600115 Bacau, Romania
d
Received 7 April 2004; revised 1 June 2004; accepted 8 June 2004
Abstract—A versatile new approach for the synthesis in three steps of 2-substituted-2,3-dihydro[1,4]dioxino[2,3-b]pyridines B via a Smiles
rearrangement using easily available reagents is described. A study illustrating the influence of experimental conditions on the progress of the
reaction is reported.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
and 1,2-dibromoethane.18 This method, unfortunately too
restrictive, not only gives unsatisfactory yield but also
makes the introduction of various substituents in the six-
membered non aromatic moiety infeasible.
The 2,3-dihydro[1,4]benzodioxin ring constitutes an
important skeletal fragment in medicinal chemistry and
hence, a variety of reports have been presented for their
synthesis and biological evaluation of compounds including
this ring.1 Some of them are antagonists of a-adrenergic
receptors, with antihypertensive properties.2–6 Other have
affinities for serotonin receptors involved in nervous
breakdown and schizophrenia7–12 or represent an attractive
therapeutic target for the treatment of glaucoma.13 More-
over, they showed additional interesting properties used for
the treatment and prevention of atherosclerosis and
oxidative injuries.14 Recently, 2,3-dihydro[1,4]benzo-
dioxins have been developed as inhibitors of 5-lipoxy-
genase, an enzyme involved in the oxygenation of
arachidonic acid to the leukotriens. They are also useful
for the treatment of inflammatory diseases such as asthma
and arthritis.15 The occurrence of the 2,3-dihydro[1,4]-
benzodioxin structure in various naturally abundant com-
pounds has been already reported.16,17
Previously, we have reported the synthesis of 2,3-
dihydro[1,4]dioxino[2,3-b]pyridine derivatives functiona-
lized at the oxygenated moiety in position 3 (A in Fig. 1).19
Compounds B (Fig. 1) substituted in position 2 were
mentioned only once and are obtained by a relatively long
synthesis implementing starting materials such as the
2-chloro-3-pyridinol and the 1-acetoxy-3-benzyloxy-2-
propanol.20 In addition, E. Matesanz et al. have recently
described a new strategy for the synthesis of 2-substituted-
2,3-dihydro[1,4]dioxino[2,3-c]pyridine and 7-substituted-
6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine developed as
potential new therapeutic agents.21
In connection with the development of new potential
5-HT1A ligands, we are interested in the study of the 2,3-
dihydro[1,4]dioxino[2,3-b]pyridine skeleton. To the best of
our knowledge, only this polyheterocyclic system has been
prepared by treatment of 3-hydroxy-2-pyridone with base
Figure 1.
In continuation of our research program concerning the
dioxinopyridines, we have reported a convenient effective
synthetic pathway to 2-substituted-2,3-dihydro-[1,4]-
dioxino[2,3-b]pyridines B22 via a Smiles rearrangement.23
A similar approach was developed by Y. J. Yoon et al. for
the synthesis of pyrido[2,3-b][1,4]oxazin-2-ones by one-pot
Keywords: 2,3-Dihydro[1,4]dioxino[2,3-b]pyridine; Smiles rearrangement;
Nucleophilic aromatic substitution.
*
Corresponding author. Tel.: þ33-2-38-41-70-73; fax: þ33-2-38-41-70-
78; e-mail address: gerald.guillaumet@univ-orleans.fr
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.041

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S. Lazar et al. / Tetrahedron 60 (2004) 6461–6473
annulation of N-substituted-2-chloroacetamides with
2-halo-3-hydroxypyridines.24 In addition, we recently
described a practical and effective synthetic route to
isomeric 2- and 3-substituted-2,3-dihydro-spiro[1,4]-
dioxino[2,3-b]pyridine amino derivatives, developed as
potential 5-HT1A ligands.25 The present paper is focused
on the extension of this preliminary work and on the study
of the influence of experimental conditions (e.g., base,
solvent, nucleofuge and substrate structure) on the progress
of the Smiles rearrangement.
reflux, affording the corresponding amino alcohols 3a–f in
good yields (Scheme 2). The reaction was carried out with
only 3 equiv. of amine.
A stirring slurry of activated commercially available Woelm
200 neutral chromatographic alumina (500 8C, 24 h)
catalyzed the regioselective opening of epoxides 2b and
2e by benzyl alcohol under mild conditions (25 8C, THF)27
to give the corresponding functionalized alcohols 4b and 4e
in satisfactory yields (Scheme 3). The similar ring opening
of epoxides 2b and 2e by N-methylbenzylamine or
benzylamine at reflux of THF gave the corresponding
amino alcohols 5b and 5e or 6b and 6e in good yields
(Scheme 3). The synthesis of the azido alcohols 7b and 7e
was achieved through the regioselectively opening of the
epoxides 2b and 2e with sodium azide, in the presence of
ammonium chloride28 (Scheme 3).
2. Results and discussion
Our strategy consists, first, in the formation of the epoxide
2a–f and then on its opening by appropriate nucleophiles to
the corresponding alcohols 3a–f, 4b, 4e, 5b, 5e, 6b, 6e, 7b
and 7e. Alcohols are the key intermediates for the synthesis
of the target molecules.
2.2. Cyclization reaction
The second part of the study concerned the cyclization of
the alcohols 3–7 by intramolecular nucleophilic aromatic
substitution (SNAr) to afford the 3-substituted-2,3-
dihydro[1,4]dioxino[2,3-b]pyridines A19d (Scheme 4,
pathway a). However, due to the selected experimental
conditions (e.g., base, solvent, nucleofuge and substrate
structure), 2-substituted-2,3-dihydro[1,4]dioxino[2,3-b]-
pyridines B (Scheme 4, pathway b) have been isolated in
fairly good yields. Formation of the isomers B could be
explained by a Smiles rearrangement involving the attack of
alkoxide on the 3-position of pyridine ring with displace-
ment of the alkoxide, and the subsequent closure of the
delivered alkoxide into the 2-position of pyridine ring.
Epoxides 2a–f, prepared by treatment of pyridinol 1a–f
with excess epichlorohydrin using NaH in DMF, were used
after purification for subsequent reactions with nucleophiles
(Scheme 1). Given the diversity of the possible means of
opening for an oxirane, it is possible to prepare compounds
bearing diversified substituents on the oxygenated moiety.
2.1. Preparation of the alcohols 3–6
Compounds containing an arylpiperazine moiety constitute
a class of important agents with a variety of pharmaco-
logical activities.26 Indeed, the ring opening of epoxide 2
with phenylpiperazine was promoted by use of THF at
Scheme 1. (a): (i) NaH, DMF, PhCH2Br, rt; 91%. (ii) MeONa, DMF, 80 8C; 92%. (iii) H2, Pd/C 10%, MeOH, rt; 85%.
Scheme 2.

S. Lazar et al. / Tetrahedron 60 (2004) 6461–6473
6463
Scheme 3.
Scheme 4.
The two A and B isomers resulting from the cyclization of
alcohols 3a–g are presented in Scheme 5.
we found that the use of the strong electron-withdrawing
nitro group as leaving group increased the yield of
rearranged product B. In the entry 5, whatever base and
solvent conditions, it was found that the total yield of the
intramolecular cyclization reaction is excellent, and conse-
quently, the isomer 8B was isolated as major product. These
results are highly interesting because they afford an access
to the isomer B in three steps starting from the pyridinols 1.
The isomers 8A and 8B were separated by flash chroma-
tography and their structures were assigned mainly based on
NMR (1D and 2D). Moreover, the structure of 8A, as a
racemic mixture, was confirmed by X-ray diffraction,
A study of conditions affecting this rearrangement was
carried out by varying different parameters such as
nucleofuge, base and solvent. The results obtained from
the cyclization reaction of alcohols 3a–g are summarized in
Table 1.
The Smiles rearrangement is facilitated when the aromatic
ring is activated by electron-withdrawing groups in the
ortho position. In fact, after extensive optimization studies,

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S. Lazar et al. / Tetrahedron 60 (2004) 6461–6473
Scheme 5. (a): AcONa, Pd/C 10%, MeOH, rt, 12 h; 90%.
Table 1. Cyclization of compounds 3
MeOH, in 90% yield. In this case, only the starting material
without any trace of the rearranged compound was obtained
by using the operating conditions described in Table 1,
entry 7.
Entry
Z
Base/solvent
T (8C)
t (h)
Products 8
(yield %)a
A
B
As can be seen from Table 1, the ratio of isomers 8A and B
varies also, with the nature of base and solvent. In entries
1–4, only one A isomer is obtained with the NaH/DME
system, except with iodine ion, while similar low yields in
rearranged product B are obtained with the t-BuOK/t-BuOH
system (entries 2–4). Note also, when different counterions
(Naþ, Liþ and Kþ) were tested, no particular influence was
noticed concerning the formation of isomer B (Table 2).
1
2
3
4
5
F
NaH/DME
t-BuOK/t-BuOH
NaH/DME
t-BuOK/t-BuOH
NaH/DME
t-BuOK/t-BuOH
NaH/DME
t-BuOK/t-BuOH
NaH/DME
80
80
80
80
80
80
80
80
80
80
80
80
48
48
72
72
48
48
48
48
12
12
72
72
58
50
62
45
67
56
65
61
30
44
5b
—
7
Cl
Br
I
—
15
—
13
8
14
59
52
—
—
NO2
t-BuOK/t-BuOH
NaH/DME
NaH/DME
6
7
OMe
H
c
c
—
Table 2. Effect of the counterion on the cyclization of the compound 3e
a
Isolated yield of each isomer after separation by flash chromatography.
The starting material was recovered in 78% yield.
Only the starting material was recovered in 75% yield.
Entry
Z
Base/solvent
T (8C)
t (h)
Products
(yield %)
b
c
A
B
clearly identifying the substitution position on the dioxine
ring (Fig. 2). In the solid state, the conformation of 8A is
quasi planar, with a dihedral angle O(15)–C(14)–C(13)–
N(10)¼2170.7(1)8. Bond lengths and angles do not show
surprising features.
1
2
3
NO2
NO2
NO2
NaH/DME
LiH/DME
KH/DME
80
80
80
12
8
4
30
37
34
59
51
50
In order to expand this study, on the basis of these results,
we selected the alcohols 4, 5, 6 and 7 with chloro and nitro
group as leaving groups to synthesize the corresponding A
and B isomers. The desired products were obtained with
satisfactory yields, by using the same conditions of
cyclization reactions (Tables 3 and 4 and Scheme 6).
When NaH was used for deprotonation of chloro-alcohols
4b, 6b and 7b (entries 1, 9 and 13, respectively), we
obtained exclusively the A product from normal ring
closure. However, a mixture of the A and B isomers was
formed upon deprotonation by using t-BuOK in t-BuOH.
Figure 2. The ORTEP drawing of 8A with thermal ellipsoids at 30% level.
After having shown the interest of the leaving group choice
for the Smiles rearrangement pathway, we tested the
feasibility of this rearrangement in absence of any leaving
group. For this purpose, the corresponding 3g alcohol was
prepared from alcohol 3b in the presence of AcONa, Pd/C in
On the other hand, when t-BuOK/t-BuOH was used for
deprotonation of 4b, 5b and 7b (entries 2, 6 and 14,
respectively) low yields of B were obtained, whereas only
traces of B were observed from alcohol 6b (entry 10).

S. Lazar et al. / Tetrahedron 60 (2004) 6461–6473
6465
Table 3. Cyclization of compounds 4, 5 and 6
Entry
Y
Z
Base/solvent
T (8C)/t (h)
Products (yield %)a
Ratiob (A/B)
1
2
3
4
5
6
7
8
OCH2Ph
Cl
NaH/DME
t-BuOK/t-BuOH
NaH/DME
t-BuOK/t-BuOH
NaH/DME
t-BuOK/t-BuOH
NaH/DME
t-BuOK/t-BuOH
NaH/DME
80/72
80/72
80/12
80/12
80/72
80/72
80/12
80/12
80/72
80/72
80/12
80/12
65
60
98
94
60
62
88
89
65
64
90
89
100/0
70/30
50/50
40/60
100/0
75/25
70/30
30/70
100/0
95/5
OCH2Ph
NO2
Cl
N(CH3)CH2Ph
N(CH3)CH2Ph
NHCH2Ph
NHCH2Ph
NO2
Cl
9
10
11
12
t-BuOK/t-BuOH
NaH/DME
t-BuOK/t-BuOH
NO2
45/55
30/70
a
Yields of cyclization reaction after flash chromatography.
Ratio of each isomer determined by 1H NMR.
b
Under similar cyclization reaction conditions the alcohols
4e–7e, with a nitro leaving group, gave a mixture of the A
and B isomers in various ratios (entries 3,7,11 and 15). Only
isomers 12A and 12B were separated by column
chromatography.
Table 4. Cyclization of compounds 7
Entry
Y
Z
Base/solvent
T (8C)/t (h)
Products
(yield %)a
A
B
By analogy with results from a completed work in 2,3-
dihydro[1,4]benzodioxin series,12 it would be also necess-
ary to have the aminomethyl or hydroxymethyl group in
position 2 of the 2,3-dihydro[1,4]dioxino[2,3-b]pyridine.
Thus, catalytic Pd/C hydrogenolysis of compounds 9, 10
and 11 in methanol with a few drops of concentrated
hydrochloric acid gave debenzylated products 13, 14 and 15
in good yields (Scheme 7).
13
14
15
16
N3
N3
Cl
NO2
NaH/DME
80/48
80/48
80/28
80/28
62
45
55
48
—
17
36
38
t-BuOK/t-BuOH
NaH/DME
t-BuOK/t-BuOH
a
Isolated yield after separation by flash chromatography.
Scheme 6.
Scheme 7.

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S. Lazar et al. / Tetrahedron 60 (2004) 6461–6473
Scheme 8.
By reaction with p-toluensulfonyl chloride in pyridine at
0 8C for 48 h the alcohols 13A and 13B afforded the
expected derivatives 16A and 16B in excellent yields. Then,
the nucleophilic replacement of the tosyl group with
methylamine in DMF at 130 8C for 8 h produced the
corresponding amines 14A and 14B.29 Under similar
sulfonation reaction conditions, the resulting amines 14A
and 14B were converted into their sulfonated derivatives
17A and 17B in good yields (Scheme 8). The sulfonation
reaction of the alcohols 13A and 13B and the N-methyl-
amines 14A and 14B was realized to prove the structure of
these isomers.
In order to formally establish the structure of these
dioxinopyridine derivatives, an X-ray analysis was per-
formed for 17A and 17B. ORTEP views of a single
molecule of 17A and 17B are depicted in Figs. 3 and 4,
respectively. In both cases, results confirmed the position of
the lateral chain on the dioxine ring. In 17A the C(9)–C(11)
Figure 3. The ORTEP drawing of 17A with thermal ellipsoids at 30% level.
˚
bond length is 1.524(5) A, similar to the corresponding
˚
C(14)–C(13) bond length in 17B [1.525(2) A]. For-
tuitously, the 17A crystal used for the X-ray study is one
enantiomer, as indicated by the spatial group (P21). The
main conformational difference between 17A and 17B
concerns the corresponding O(10)–C(9)–C(11)–N(12) and
O(19)–C(14)–C(13)–N(11) dihedral angles, found at
59.9(2)8 for 17A and 2164.7(2)8 for 17B, respectively.
On the other hand, bond lengths and angles do not show
surprising features. The X-ray data of 17A and 17B
confirmed indirectly the structure of the alcohols 13A and
13B and the N-methylamines 14A and 14B.
As N-alkylated compounds are susceptible to present
interesting biological proprieties, we decided to
regenerate the free primary 2-(2,3-dihydro[1,4]-
dioxino[2,3-b]pyridine)ylmethylamines 15A and 15B.
Hence, the direct conversion of compounds 12 into the
corresponding amines 15 was achieved by catalytic
hydrogenation (Scheme 9).
Figure 4. The ORTEP drawing of 17B with thermal ellipsoids at 30% level.
The isomeric mixtures (13Aþ13B), (14Aþ14B) and
(15Aþ15B) were separated by column chromatography
after debenzylation of compounds 9, 10 and 11,
respectively.
These free amines 15A and 15B offer many possibilities for
Scheme 9.

S. Lazar et al. / Tetrahedron 60 (2004) 6461–6473
6467
Scheme 10.
further reactions. For example, the direct alkylation of these
amines, with N,N-bis(2-chloroethyl)aniline in the presence
of sodium hydrogen carbonate and sodium iodide in
ethylene glycol afforded the expected dioxinopyridine
derivatives 8A and 8B in 69%, 65% yields, respectively
(Scheme 10). Moreover, this sequence allows to confirm the
structures of 12A, 12B, and also of 15A, 15B.
phere. All organic solvents were distilled immediately prior
to use, and magnesium sulfate was used for drying solutions
of organic solvents.
The crystal structures of 8A, 17A and 17B have been
determined by single-crystal X-ray diffraction techniques.
Diffraction data were collected using a CAD4 Enraf–
Nonius diffractometer with graphite monochromatized
Cu Ka radiation. The cell parameters were determined by
least-squares from the setting angles for 25 reflexions. An
empirical absorption correction was applied. The data were
also corrected for Lorentz and polarization effect. The
positions of non-H atoms were determined by the program
SHELXS 8630 and the position of the H atoms were
included for structure factor calculations but not refined.
3. Conclusion
In summary, using easily available reagents, we have
developed a convenient strategy that gave access in
satisfactory yields to the corresponding 2- and 3-substi-
tuted-2,3-dihydro[1,4]dioxino[2,3-b]pyridines (A and B). In
comparison with classical synthesis of 3-substituted deriva-
tives A by nucleophilic aromatic substitution (SNAr), the
access to 2-substituted-2,3-dihydro[1,4]dioxino[2,3-b]pyri-
dines B was realized in three steps via a Smiles
rearrangement. By studying the influence of experimental
conditions on the progress of the reaction we observed that
the Smiles rearrangement is facilitated by activation of the
aromatic ring by electron-withdrawing groups in the ortho
position, for example, the use of the strong electron-
withdrawing nitro group as leaving group increased the
yield of rearranged product B. The functionalisation of these
compounds in 2 or 3 position with aminomethyl or
hydroxymethyl groups could be of potential utility for
further developments in medicinal chemistry.
For 8A, the crystal is monoclinic, space group P21/n, with
˚
˚
˚
a¼7.414(10) A, b¼7.005(4) A, c¼30.370(4) A, b¼
90.94(1)8, and Z¼4. A crystal 0.15£0.50£0.60 was chosen.
For 17A, the crystal is monoclinic, space group P21, with
˚
˚
˚
a¼8.107(1) A, b¼6.179(1) A, c¼15.753(1) A, b¼
92.74(1)8, and Z¼2. A crystal 0.37£0.20£0.12 mm
was chosen. For 17B, the crystal is monoclinic, space
˚
˚
group P21/c with a¼19.653(4) A, b¼5.828(1) A,
˚
c¼15.069(2) A, b¼112.33(2)8, and Z¼4. A crystal
0.37£0.25£0.12 mm was chosen.
The X-ray results confirm the structure as anticipated on the
basis of 13C and 1H NMR data. Full crystallographic results
have been deposited at the Cambridge Crystallographic
Data Center (CCDC), UK, as Supplementary Materials.31
4. Experimental
4.1. General procedure for the preparation of the
epoxides 2a–f
Melting points were determined in capillary tubes with
¨
Bu¨chi SMP-20 or on a Kofler apparatus and are uncorrected.
IR spectra were obtained on Perkin–Elmer Paragon 1000
To a stirred suspension of NaH (5.33 g of 60% oil
dispersion, 158.60 mmol) in DMF (50 mL) was added
dropwise a solution of appropriate pyridinol 1a–f
(132 mmol) in DMF (50 mL). After 45 min, a solution of
epichlorohydrin (103.5 mL, 1.32 mol) in DMF (25 mL) was
added and the mixture was stirred at 60 8C during 72 h.
After cooling to room temperature, the DMF was evapor-
ated to dryness. The residue was washed with H2O and
extracted with AcOEt. The organic layer was dried over
MgSO4, evaporated and purified by column chromatog-
raphy (eluent: AcOEt/petroleum ether, 1:1) to give the
corresponding epoxides 2a–f.
1
PC FT-IR. H and 13C NMR spectra were, respectively,
recorded at 250 and 62.9 MHz on Bruker Avance DPX250.
Chemical shifts (d values) were reported in ppm and
coupling constants (J values) in Hz. Me4Si was the internal
standard. Elemental analyses were performed by CNRS
laboratory (Vernaison, France). Microanalyses for the
elements indicated were within 0.3% of theoretical values.
MS data were taken on a Perkin–Elmer SCIEX type API
300. TLC and flash chromatography separations were,
respectively, performed on silica gel (Merck 60 F254) plates
and on silica gel (Merck 60, 230–400 mesh) columns.
Commercial reagents were used as received without
additional purification. All reactions involving moisture-
sensitive reagents were performed under an argon atmos-
4.1.1. 2-Fluoro-3-oxiranylmethoxypyridine 2a. Oil; IR
1
(film) n 1289 (C–O–C) cm21; H NMR (CDCl3) d 2.78

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S. Lazar et al. / Tetrahedron 60 (2004) 6461–6473
(dd, 1H, J¼2.6, 4.8 Hz, Ar-O–CH2–CH–CH2), 2.93 (t, 1H,
J¼4.8 Hz, Ar-O–CH2–CH–CH2), 3.34–3.43 (m, 1H,
CH2–CH–CH2), 4.00 (dd, 1H, J¼6.1, 11.4 Hz, Ar-O–
CH2), 4.40 (dd, 1H, J¼2.6, 11.4 Hz, Ar-O–CH2), 7.14 (ddd,
1H, J¼0.8, 4.9, 7.9 Hz, Hb), 7.33–7.45 (m, 1H, Hg), 7.76
(dt, 1H, J¼3.2, 4.9 Hz, Ha); 13C NMR (CDCl3) d 44.1, 50.1,
71.2, 118.0, 124.6, 142.2, 142.3, 153.9; MS (CI) m/z 170
(Mþ1); Anal. calcd for C8H8FNO2: C, 56.80; H, 4.77; N,
8.28. Found: C, 56.91; H, 4.80; N, 8.39.
3.35 (m, 1H, CH2–CH–CH2), 3.88–3.98 (m, 4H, Ar-O–
CH2, CH3), 4.22 (dd, 1H, J¼3.1, 11.3 Hz, Ar-O–CH2), 6.76
(dd, 1H, J¼5.0, 7.8 Hz, Hb), 7.07 (dd, 1H, J¼1.6, 7.8 Hz
Hg), 7.70 (dd, 1H, J¼1.6, 5.0 Hz, Ha); 13C NMR (CDCl3) d
44.7, 50.0, 53.5, 69.9, 116.7, 119.9, 138.1, 143.0, 154.8; MS
(CI) m/z 182 (Mþ1); Anal. calcd for C9H11NO3: C, 59.66;
H, 6.12; N, 7.73. Found: C, 59.71; H, 6.30; N, 7.79.
4.2. General procedure for the preparation of the
alcohols 3a–f
4.1.2. 2-Chloro-3-oxiranylmethoxypyridine 2b. Mp 35–
36 8C; IR (KBr) n 1280 and 1200 (C–O–C) cm21; 1H NMR
(CDCl3) d 2.83 (dd, 1H, J¼2.7, 4.9 Hz, Ar-O–CH2–CH–
CH2), 2.94 (t, 1H, J¼4.9 Hz, Ar-O–CH2–CH–CH2), 3.36–
3.44 (m, 1H, CH2–CH–CH2), 4.04 (dd, 1H, J¼5.4,
11.4 Hz, Ar-O–CH2), 4.39 (dd, 1H, J¼2.8, 11.3 Hz, Ar-
O–CH2), 7.20 (dd, 1H, J¼4.7, 8.2 Hz, Hb), 7.30 (dd, 1H,
1.6, 8.2 Hz, Hg), 8.01 (dd, 1H, J¼1.6, 4.7 Hz, Ha); 13C
NMR (CDCl3) d NMR (CDCl3) d 44.1, 49.7, 69.5, 120.8,
123.2, 140.8, 141.0, 150.5; MS (CI) m/z 186 (Mþ1); Anal.
calcd for C8H8ClNO2: C, 51.77; H, 4.34; N, 7.55. Found: C,
51.81; H, 4.42; N, 7.69.
To a solution of appropriate epoxides 2a–f (6.73 mmol) in
THF (30 mL) was added 1-phenylpiperazine (20 mmol).
The mixture was stirred at reflux for 24 h then diluted with
H2O, extracted with AcOEt, dried over MgSO4 and the
solvent removed in vacuo to give the crude product. This
was purified by column chromatography (eluent: MeOH/
CH2Cl2, 1:9) to afford the corresponding alcohols 3a–f.
4.2.1. 1-(2-Fluoropyridin-3-yloxy)-3-(4-phenylpiperazin-
1-yl)-propan-2-ol 3a. Oil; IR (film) n 3500–3200 (OH),
1
1286 (C–O–C) cm21; H NMR (CDCl3) d 2.49–2.68 (m,
4H, CH2–N(CH2)2), 2.72–2.84 (m, 2H, CH–CH2–N),
3.10–3.24 (m, 4H, Ph-N(CH2)2), 3.98–4.20 (m, 4H,
O–CH2–CH–OH), 6.77–6.95 (m, 3H, Hg, HAr), 7.07
(ddd, 1H, J¼0.8, 4.9, 7.8 Hz, Hb), 7.17–7.38 (m, 3H, Har),
7.71 (dd, 1H, J¼1.7, 4.9 Hz, Ha); 13C NMR (CDCl3) d 49.0,
53.2, 60.1, 65.5, 71.5, 115.9, 119.7, 122.4, 124.4, 129.1,
141.8, 142.2, 151.0, 154.0; MS (CI) m/z 332 (Mþ1); Anal.
calcd for C18H22FN3O2: C, 65.24; H, 6.69; N, 12.68. Found:
C, 65.33; H, 6.80; N, 12.76.
4.1.3. 2-Bromo-3-oxiranylmethoxypyridine 2c. Mp 50–
51 8C; IR (KBr) n 1294 (C–O–C) cm21; 1H NMR (CDCl3)
d 2.78 (dd, 1H, J¼2.7, 4.9 Hz, Ar-O–CH2–CH–CH2), 2.86
(t, 1H, J¼4.9 Hz, Ar-O–CH2–CH–CH2), 3.28–3.37 (m,
1H, CH2–CH–CH2), 3.96 (dd, 1H, J¼5.5, 11.4 Hz, Ar-O–
CH2), 4.33 (dd, 1H, J¼2.7, 11.4 Hz, Ar-O–CH2), 7.10–
7.19 (m, 2H, Hb, Hg), 7.92 (dd, 1H, J¼2.7, 3.7 Hz, Ha); 13
C
NMR (CDCl3) d 44.3, 49.8, 69.6, 120.4, 123.5, 132.9, 141.8,
151.9; MS (CI) m/z 230 (Mþ1 for 79Br) and 232 (Mþ1 for
81Br); Anal. calcd for C8H8BrNO2: C, 41.77; H, 3.51; N,
6.09. Found: C, 41.91; H, 3.60; N, 6.15.
4.2.2. 1-(2-Chloropyridin-3-yloxy)-3-(4-phenylpipera-
zin-1-yl)-propan-2-ol 3b. Mp 107–108 8C; IR (KBr) n
;
3500–3200 (OH), 1284 and 1209 (C–O–C) cm21 1H
4.1.4. 2-Iodo-3-oxiranylmethoxypyridine 2d. Oil; IR
1
NMR (CDCl3) d 2.58–2.73 (m, 4H, CH2–N(CH2)2), 2.79–
2.91 (m, 2H, CH–CH2–N), 3.17–3.28 (m, 4H,
Ph-N(CH2)2), 4.06–4.24 (m, 4H, O–CH2–CH–OH),
6.81–6.96 (m, 3H, Hg, HAr), 7.19 (dd, 1H, J¼4.7, 8.1 Hz,
Hb), 7.23–7.32 (m, 3H, Har), 8.00 (dd, 1H, J¼1.5, 4.7 Hz,
Ha); 13C NMR (CDCl3) d 49.4, 53.5, 60.4, 65.7, 71.5, 116.3,
120.1, 120.9, 123.3, 129.3, 141.1, 151.2, 151.3; MS (CI) m/z
348 (Mþ1); Anal. calcd for C18H22ClN3O2: C, 62.15; H,
6.38; N, 12.08. Found: C, 62.33; H, 6.45; N, 12.16.
(film) n 1285 (C–O–C) cm21; H NMR (CDCl3) d 2.79–
2.88 (m, 2H, Ar-O–CH2–CH–CH2), 3.27–3.37 (m, 1H,
CH2–CH–CH2), 3.95 (dd, 1H, J¼5.3, 11.4 Hz, Ar-O–
CH2), 4.32 (dd, 1H, J¼2.4, 11.4 Hz, Ar-O–CH2), 7.00 (dd,
1H, J¼1.6, 8.2 Hz, Hg), 7.11 (dd, 1H, J¼4.6, 8.2 Hz, Hb),
7.91 (dd, 1H, J¼1.6, 4.6 Hz, Ha); 13C NMR (CDCl3) d 44.2,
49.6, 69.3, 111.7, 118.5, 123.5, 142.8, 153.9; MS (CI) m/z
278 (Mþ1); Anal. calcd for C8H8INO2: C, 34.68; H, 2.91;
N, 5.06. Found: C, 34.72; H, 3.03; N, 5.19.
4.2.3. 1-(2-Bromopyridin-3-yloxy)-3-(4-phenylpipera-
zin-1-yl)-propan-2-ol 3c. Mp 84–85 8C; IR (KBr) n
4.1.5. 2-Nitro-3-oxiranylmethoxypyridine 2e. Mp 52–
53 8C; IR (KBr) n 1256 and 1170 (C–O–C) cm21; 1H NMR
(CDCl3) d 2.79 (dd, 1H, J¼2.8, 4.6 Hz, Ar-O–CH2–CH–
CH2), 2.91 (t, 1H, J¼4.6 Hz, Ar-O–CH2–CH–CH2), 3.31–
3.41 (m, 1H, CH2–CH–CH2), 4.10 (dd, 1H, J¼5.6,
11.6 Hz, Ar-O–CH2), 4.49 (dd, 1H, J¼2.5, 11.6 Hz,
Ar-O–CH2), 7.52 (dd, 1H, J¼4.4, 8.5 Hz, Hb), 7.62 (dd,
3500–3200 (OH), 1291 (C–O–C) cm21
;
1H NMR
(CDCl3) d 2.53–2.70 (m, 4H, CH2–N(CH2)2), 2.72–2.85
(m, 2H, CH–CH2–N), 3.08–3.25 (m, 4H, Ph-N(CH2)2),
3.98–4.22 (m, 4H, O–CH2–CH–OH), 6.78–6.95 (m, 3H,
Hb, HAr), 7.11–7.30 (m, 4H, Hg, Har), 7.94 (dd, 1H, J¼1.4,
4.8 Hz, Ha); 13C NMR (CDCl3) d 49.1, 53.3, 60.3, 65.5,
71.4, 116.0, 119.7, 120.1, 123.4, 129.0, 132.9, 141.5, 151.0,
152.1; MS (CI) m/z 392 (Mþ1 for 79Br) and 394 (Mþ1 for
81Br); Anal. calcd for C18H22BrN3O2: C, 55.11; H, 5.65; N,
10.71. Found: C, 55.23; H, 5.80; N, 10.76.
1H, 1.3, 8.5 Hz, Hg), 8.09 (dd, 1H, J¼1.3, 4.4 Hz, Ha); 13
C
NMR (CDCl3) d 44.4, 49.8, 70.4, 124.6, 128.8, 140.0,
146.9; MS (CI) m/z 197 (Mþ1); Anal. calcd for C8H8N2O4:
C, 48.98; H, 4.11; N, 14.28. Found: C, 49.11; H, 4.23; N,
14.39.
4.2.4. 1-(2-Iodopyridin-3-yloxy)-3-(4-phenylpiperazin-1-
yl)-propan-2-ol 3d. Mp 93–94 8C; IR (KBr) n 3500–3200
4.1.6. 2-Methoxy-3-oxiranylmethoxypyridine 2f. Mp 31–
32 8C; IR (KBr) n 1283 and 1197 (C–O–C) cm21; 1H NMR
(CDCl3) d 2.68 (dd, 1H, J¼2.6, 4.8 Hz, Ar-O–CH2–CH–
CH2), 2.84 (t, 1H, J¼4.8 Hz, Ar-O–CH2–CH–CH2), 3.27–
1
(OH), 1284 (C–O–C) cm21; H NMR (CDCl3) d 2.60–
2.79 (m, 4H, CH2–N(CH2)2), 2.81–2.94 (m, 2H, CH–
CH2–N), 3.16–3.35 (m, 4H, Ph-N(CH2)2), 4.05–4.26 (m,

S. Lazar et al. / Tetrahedron 60 (2004) 6461–6473
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4H, O–CH2–CH–OH), 6.83–6.98 (m, 3H, Hb, HAr), 7.03–
7.10 (m, 1H, Hg), 7.16–7.32 (m, 3H, Har), 7.94 (dd, 1H,
J¼1.2, 5.4 Hz, Ha); 13C NMR (CDCl3) d 49.3, 53.5, 60.5,
65.7, 71.5, 112.4, 116.2, 118.4, 120.0, 123.6, 129.2, 143.1,
151.2, 154.5; MS (CI) m/z 440 (Mþ1); Anal. calcd for
C18H22IN3O2: C, 49.21; H, 5.05; N, 9.57. Found: C, 49.19;
H, 5.11; N, 9.47.
4.06–4.26 (m, 4H, Ar-O–CH2–CH–OH), 4.51 (s, 2H,
Ph-CH2), 7.20–7.35 (m, 5H, Har), 7.47 (dd, 1H, J¼4.1,
8.4 Hz, Hb), 7.52 (dd, 1H, J¼1.6, 8.4 Hz, Hg), 8.03 (dd, 1H,
J¼1.6, 4.1 Hz, Ha); 13C NMR (CDCl3) d 68.5, 70.3, 70.7,
73.5, 124.3, 127.8, 127.9, 128.4, 129.0, 137.6, 139.4, 147.2,
148.5; MS (CI) m/z 305 (Mþ1); Anal. calcd for
C15H16N2O5: C, 59.21; H, 5.30; N, 9.21. Found: C, 59.17;
H, 5.42; N, 9.19.
4.2.5. 1-(2-Nitropyridin-3-yloxy)-3-(4-phenylpiperazin-
1-yl)-propan-2-ol 3e. Mp 102–103 8C; IR (KBr) n 3500–
4.4. Preparation of the amino alcohols 5 and 6
1
3200 (OH), 1537 (NO2), 1275 (C–O–C) cm21; H NMR
(CDCl3) d 2.49–2.70 (m, 4H, CH2–N(CH2)2), 2.72–2.85
(m, 2H, CH–CH2–N), 3.10–3.25 (m, 4H, Ph-N(CH2)2),
4.08–4.30 (m, 4H, O–CH2–CH–OH), 6.79–6.98 (m, 3H,
HAr), 7.18–7.35 (m, 2H, Har), 7.50 (dd, 1H, J¼4.4, 8.5 Hz,
Hb), 7.60 (dd, 1H, J¼1.3, 8.5 Hz, Hg), 8.05 (dd, 1H, J¼1.3,
4.4 Hz, Ha); 13C NMR (CDCl3) d 48.9, 53.1, 59.8, 65.4,
71.7, 115.9, 119.6, 124.3, 128.8, 128.9, 139.2, 147.2, 148.4,
150.9; MS (CI) m/z 359 (Mþ1); Anal. calcd for
C18H22N4O4: C, 60.32; H, 6.19; N, 15.63. Found: C,
60.23; H, 6.27; N, 15.56.
Following the procedure described for 3a–f but substituting
1-phenylpiperazine by (20 mmol) of N-methylbenzylamine
or benzylamine, the epoxide 2b and 2e gave the correspond-
ing amino alcohol 5b (90%), 5e (82%), 6b (76%) or 6e
(89%).
4.4.1. 1-(N-Benzyl-N-methylamino)-3-(2-chloropyridin-
3-yloxy)-propan-2-ol 5b. Oil; IR (film) n 3500–3200
(OH), 1291 and 1207 (C–O–C) cm21; 1H NMR (CDCl3) d
2.30 (s, 3H, CH3), 2.58 (dd, 1H, J¼4.4, 12.2 Hz, CH–CH2–
N), 2.70 (dd, 1H, J¼9.1, 12.2 Hz, CH–CH2–N), 3.53 (d,
1H, J¼12.9 Hz, O–CH2–CH), 3.69 (d, 1H, J¼12.9 Hz,
O–CH2–CH), 4.00–4.06 (m, 2H, CH2-Ph), 4.08–4.20 (m,
2H, CH–OH), 7.11–7.40 (m, 7H, Hb, Hg, Har), 7.98 (dt, 1H,
J¼1.3, 4.4 Hz, Ha); 13C NMR (CDCl3) d 42.5, 59.2, 62.6,
66.1, 71.4, 120.7, 123.2, 127.4, 128.4, 129.1, 138.2, 140.8,
141.2, 151.1; MS (CI) m/z 307 (Mþ1); Anal. calcd for
C16H19ClN2O2: C, 62.64; H, 6.24; N, 9.13. Found: C, 62.53;
H, 6.30; N, 9.16.
4.2.6. 1-(2-Methoxypyridin-3-yloxy)-3-(4-phenylpipera-
zin-1-yl)-propan-2-ol 3f. Oil; IR (film) n 3500–3100
1
(OH), 1260 (C–O–C) cm21; H NMR (CDCl3) d 2.50–
2.68 (m, 4H, CH2–N(CH2)2), 2.70–2.84 (m, 2H, CH–
CH2–N), 3.08–3.30 (m, 4H, Ph-N(CH2)2), 3.94–4.26 (m,
4H, O–CH2–CH–OH), 6.75–6.98 (m, 4H, Hb, HAr), 7.05–
7.15 (m, 1H, Hg), 7.19–7.35 (m, 2H, Har), 7.75 (dd, 1H,
J¼1.3, 4.4 Hz, Ha); 13C NMR (CDCl3) d 49.0, 53.2, 53.3,
60.4, 71.5, 115.9, 116.6, 119.5, 119.6, 130.0, 137.6, 143.2,
151.0, 154.7; MS (CI) m/z 344 (Mþ1); Anal. calcd for
C19H25N3O3: C, 66.45; H, 7.34; N, 12.24. Found: C, 66.53;
H, 7.40; N, 12.16.
4.4.2. 1-(N-Benzyl-N-methylamino)-3-(2-nitropyridin-3-
yloxy)-propan-2-ol 5e. Oil; IR (film) n 3500–3200 (OH),
1
1280 and 1190 (C–O–C) cm21; H NMR (CDCl3) d 2.24
(s, 3H, CH3), 2.52 (dd, 1H, J¼4.7, 12.5 Hz, CH–CH2–N),
2.63 (dd, 1H, J¼8.0, 12.5 Hz, CH–CH2–N), 3.50 (d, 1H,
J¼13.0 Hz, O–CH2–CH), 3.61 (d, 1H, J¼13.0 Hz,
O–CH2–CH), 4.01–4.20 (m, 4H, CH2-Ph, CH–OH),
7.16–7.33 (m, 5H, Har), 7.48 (dd, 1H, J¼4.4, 8.4 Hz, Hb),
7.57 (dd, 1H, 1.3, 8.4 Hz, Hg), 8.02 (dd, 1H, J¼1.3, 4.4 Hz,
Ha); 13C NMR (CDCl3) d 42.2, 58.8, 62.3, 66.0, 71.8, 124.3,
127.1, 128.2, 128.8, 128.9, 138.0, 139.1, 147.2, 148.4; MS
(CI) m/z 318 (Mþ1); Anal. calcd for C16H19N3O4: C, 60.56;
H, 6.03; N, 13.24. Found: C, 60.53; H, 6.00; N, 13.36.
4.3. Preparation of the alcohols 4
Epoxide 2b or 2e (5.38 mmol) was allowed to react in THF
(50 mL) with 34 g of Woelm-200-neutral dehydrated
alumina (500 8C, 24 h) doped with benzyl alcohol
(5.6 mL, 53.80 mmol) for 1.5 h at room temperature. After
the appropriate amount of time had elapsed, the slurry was
filtered through a sintered glass funnel containing a Celite
pad, and the collected alumina was washed with additional
MeOH. The combined washings were concentrated, and the
residue was purified by column chromatography (eluent:
MeOH/CH2Cl2, 1:9) to leave the alcohol 4b (60%) or 4e
(60%).
4.4.3. 1-(N-Benzylamino)-3-(2-chloropyridin-3-yloxy)-
propan-2-ol 6b. Mp 65–66 8C; IR (KBr) n 3600–3200
;
(OH, NH), 1285 and 1205 (C–O–C) cm21 1H NMR
(CDCl3) d 2.83 (dd, 1H, J¼7.4, 12.1 Hz, CH–CH2–N),
2.92 (dd, 1H, J¼7.4, 12.1 Hz, CH–CH2–N), 3.35 (broad s,
2H, OH, NH), 3.77–3.92 (m, 2H, O–CH2–CH), 4.00–4.06
(m, 2H, CH2-Ph), 4.09–4.19 (m, 2H, CH–OH), 7.11–7.20
(m, 2H, Hb, Hg), 7.21–7.39 (m, 5H, Har), 7.98 (dd, 1H,
J¼2.0, 4.2 Hz, Ha); 13C NMR (CDCl3) d 51.0, 53.7, 67.8,
71.9, 120.7, 123.3, 127.4, 128.4, 128.6, 139.2, 140.9, 141.0,
151.0; MS (CI) m/z 293 (Mþ1); Anal. calcd for
C15H17ClN2O2: C, 61.54; H, 5.85; N, 9.57. Found: C,
61.62; H, 5.80; N, 9.76.
4.3.1. 1-Benzyloxy-3-(2-chloropyridin-3-yloxy)-propan-
1
2-ol 4b. Oil; IR (film) n 3500–3200 (OH) cm21; H NMR
(CDCl3) d 3.71 (d, 2H, J¼5.6 Hz, Ph-CH2–O–CH2), 4.08–
4.33 (m, 4H, Ar-O–CH2–CH–OH), 4.58 (s, 2H, Ph-CH2),
7.15–7.38 (m, 7H, Hb, Hg, HAr), 8.00 (dd, 1H, J¼1.9,
4.4 Hz, Ha); 13C NMR (CDCl3) d 68.9, 70.2, 70.6, 73.7,
120.8, 123.3, 127.9, 128.0, 128.6, 137.7, 141.0, 141.1,
150.9; MS (CI) m/z 294 (Mþ1); Anal. calcd for
C15H16ClNO3: C, 61.33; H, 5.49; N, 4.77. Found: C,
61.41; H, 5.40; N, 4.67.
4.4.4. 1-(N-Benzylamino)-3-(2-nitropyridin-3-yloxy)-
propan-2-ol 6e. Oil; IR (film) n 3600–3200 (OH, NH),
1280 and 1210 (C–O–C) cm21; 1H NMR (CDCl3) d 2.76–
2.94 (m, 4H, OH, NH, CH–CH2–N), 3.83 (dd, 2H, J¼13.4,
4.3.2. 1-Benzyloxy-3-(2-nitropyridin-3-yloxy)-propan-2-
ol 4e. Mp 74–75 8C; IR (KBr) n 3500–3200 (OH) cm21; 1H
NMR (CDCl3) d 3.61 (d, 2H, J¼4.7 Hz, Ph-CH2–O–CH2),

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S. Lazar et al. / Tetrahedron 60 (2004) 6461–6473
16.5 Hz, CH2–Ph), 4.01–4.11 (m, 2H, CH–OH), 4.13–
4.22 (m, 2H, O–CH2–CH), 7.21–7.38 (m, 5H, Har), 2.92
(dd, 1H, J¼7.4, 12.1 Hz, CH–CH2–N), 3.35 (broad s, 2H,
OH, NH), 7.52 (dd, 1H, J¼4.1, 8.5 Hz, Hb), 7.57 (dd, 1H,
J¼1.7, 8.5 Hz, Hg), 8.10 (dd, 1H, J¼1.7, 4.1 Hz, Ha); 13C
NMR (CDCl3) d 50.8, 53.9, 67.9, 72.5, 124.3, 127.3, 128.3,
128.6 128.9, 139.7, 139.8, 147.5; MS (CI) m/z 304 (Mþ1);
Anal. calcd for C15H17N3O4: C, 59.40; H, 5.65; N, 13.85.
Found: C, 59.49; H, 5.80; N, 13.76.
4.6.1. 3-(4-Phenylpiperazin-1-ylmethyl)-2,3-di-
hydro[1,4]dioxino[2,3-b]pyridine 8A. Mp 119–120 8C;
IR (KBr) n 1270 and 1240 (C–O–C) cm21 1H NMR
;
(CDCl3) d 2.64–2.87 (m, 6H, CH2–N(CH2)2), 3.13–3.29
(m, 4H, Ph-N(CH2)2), 4.03 (dd, 1H, J¼7.5, 11.5 Hz,
O–CH2–CH), 4.35 (dd, 1H, J¼2.3, 11.5 Hz, O–CH2–
CH), 4.46–4.57 (m, 1H, O–CH2–CH), 6.81–6.96 (m, 4H,
Hb, Har), 7.18 (dd, 1H, J¼1.6, 7.8 Hz, Hg), 7.21–7.31 (m,
2H, Har), 7.82 (dd, 1H, J¼1.6, 4.8 Hz, Ha); 13C NMR
(CDCl3) d 49.3, 54.2, 58.4, 66.6, 72.7, 116.2, 118.5, 119.9,
124.7, 129.2, 139.1, 140.2, 150.9, 151.3; MS (CI) m/z 312
(Mþ1); Anal. calcd for C18H21N3O2: C, 69.43; H, 6.80; N,
13.49. Found: C, 69.31; H, 6.75; N, 13.36.
4.5. Preparation of the azido alcohols 7
A solution of epoxide 2b or 2e (10.76 mmol) in MeOH
(42 mL) and H2O (6 mL) was treated with NaN3 (2.10 g,
32.40 mmol) and NH4Cl (1.40 g, 25.80 mmol). The mixture
was heated at reflux for 24 h, cooled and the solvent
removed in vacuo. The residue was partitioned between
H2O and CH2Cl2. The aqueous layer was further extracted
with AcOEt. The combined organic layers were dried
(MgSO4) and the solvent removed in vacuo to give crude
product. This was purified by column chromatography
(eluent: MeOH/CH2Cl2, 1:9) to afford the azido alcohol 7b
(88%) or 7e (80%).
4.6.2. 2-(4-Phenylpiperazin-1-ylmethyl)-2,3-di-
hydro[1,4]dioxino[2,3-b]pyridine 8B. Oil; IR (film) n
;
1277 and 1247 (C–O–C) cm21 1H NMR (CDCl3) d
2.60–2.82 (m, 6H, CH2–N(CH2)2), 3.17–3.26 (m, 4H, Ph-
N(CH2)2), 4.20 (dd, 1H, J¼7.4, 11.4 Hz, O–CH2–CH),
4.31–4.41 (m, 1H, O–CH2–CH), 4.52 (dd, 1H, J¼2.2,
11.4 Hz, O–CH2–CH), 6.80–6.97 (m, 4H, Hb, Har), 7.20
(dd, 1H, J¼1.6, 7.8 Hz, Hg), 7.25–7.31 (m, 2H, Har), 7.82
(dd, 1H, J¼1.6, 4.7 Hz, Ha); 13C NMR (CDCl3) d 49.2,
54.0, 58.3, 67.5, 71.2, 116.2, 118.6, 119.9, 125.0, 129.2,
138.8, 140.0, 151.0, 151.3; MS (CI) m/z 312 (Mþ1); Anal.
calcd for C18H21N3O2: C, 69.43; H, 6.80; N, 13.49. Found:
C, 69.39; H, 6.77; N, 13.56.
4.5.1. 1-Azido-3-(2-chloropyridin-3-yloxy)-propan-2-ol
7b. Oil; IR (film) n 3400–3200 (OH), 2095 (N3), 1280
1
and 1205 (C–O–C) cm21; H NMR (CDCl3) d 3.51–3.68
(m, 2H, Ar-O–CH2), 4.10 (d, 2H, J¼5.4 Hz, CH2–N3),
4.20–4.32 (m, 2H, CH–OH), 7.18–7.30 (m, 2H, Hb, Hg),
8.02 (dd, 1H, J¼2.0, 4.3 Hz, Ha); 13C NMR (CDCl3) d 53.3,
68.9, 70.3, 121.0, 123.4, 141.0, 141.3, 150.7; MS (CI) m/z
229 (Mþ1); Anal. calcd for C8H9ClN4O2: C, 42.03; H, 3.97;
N, 24.50. Found: C, 42.19; H, 3.80; N, 24.36.
4.6.3. 3-Benzyloxymethyl-2,3-dihydro[1,4]dioxino[2,3-
b]pyridine 9A. Mp 84–85 8C; IR (KBr) n 1281 and 1240
(C–O–C) cm21; 1H NMR (CDCl3) d 3.71 (dd, 1H, J¼6.4,
10.2 Hz, Ph-CH2–O–CH2), 3.83 (dd, 1H, J¼4.5, 10.2 Hz,
Ph-CH2–O–CH2), 4.09 (dd, 1H, J¼7.5, 11.6 Hz, O–CH2–
CH), 4.33 (dd, 1H, J¼2.3, 11.6 Hz, O–CH2–CH), 4.45–
4.55 (m, 1H, O–CH2–CH), 4.59 (s, 2H, Ph-CH2–O),
6.84 (dd, 1H, J¼4.7, 7.8 Hz, Hb), 7.17 (dd, 1H, J¼1.6,
7.8 Hz, Hg), 7.25–7.40 (m, 5H, Har), 7.81 (dd, 1H, J¼1.6,
4.7 Hz, Ha); 13C NMR (CDCl3) d 65.4, 68.3, 73.0, 73.8,
118.5, 124.7, 127.8, 127.9, 128.5, 137.6, 139.0, 140.1,
150.8; MS (CI) m/z 258 (Mþ1); Anal. calcd for C15H15NO3:
C, 70.02; H, 5.88; N, 5.44. Found: C, 70.17; H, 5.80; N,
5.56.
4.5.2. 1-Azido-3-(2-nitropyridin-3-yloxy)-propan-2-ol
7e. Mp 77–78 8C; IR (KBr) n 3400–3200 (OH), 2098
(N3), 1265 (C–O–C) cm21; 1H NMR (CDCl3) d 3.25–3.44
(m, 2H, Ar-O–CH2), 3.95–4.08 (m, 2H, CH–OH), 4.14–
4.27 (m, 2H, CH2–N3), 7.75 (dd, 1H, J¼4.5, 8.5 Hz, Hb),
7.99 (dd, 1H, J¼1.3, 8.5 Hz, Hg), 8.10 (dd, 1H, J¼1.3,
4.5 Hz, Ha); 13C NMR (CDCl3) d 53.3, 68.3, 71.2, 125.9,
130.3, 140.0, 146.8, 148.7; MS (CI) m/z 240 (Mþ1); Anal.
calcd for C8H9N5O4: C, 40.17; H, 3.79; N, 29.28. Found: C,
40.33; H, 3.80; N, 29.36.
4.6.4. 2-Benzyloxymethyl-2,3-dihydro[1,4]dioxino[2,3-
b]pyridine 9B. IR (film) n 1281 and 1185 (C–O–C)
1
4.6. General procedure for the preparation of
dioxinopyridines 8–12
cm21; H NMR (CDCl3) d 3.67 (dd, 1H, J¼5.3, 10.4 Hz,
Ph-CH2–O–CH2), 3.75 (dd, 1H, J¼4.8, 10.4 Hz, Ph-CH2–
O–CH2), 4.27 (dd, 1H, J¼7.2, 11.0 Hz, O–CH2–CH),
4.31–4.43 (m, 1H, O–CH2–CH), 4.48 (dd, 1H, J¼1.9,
11.0 Hz, O–CH2–CH), 4.90 (s, 2H, Ph-CH2–O), 6.86 (dd,
1H, J¼4.7, 7.8 Hz, Hb), 7.20 (dd, 1H, J¼1.6, 7.8 Hz, Hg),
7.28–7.45 (m, 5H, Har), 7.82 (dd, 1H, J¼1.6, 4.7 Hz, Ha);
13C NMR (CDCl3) d 66.3, 68.3, 72.1, 73.9, 118.7, 125.0,
127.9, 128.1, 128.7, 137.3, 138.9, 140.0, 150.9; MS (CI) m/z
258 (Mþ1); Anal. calcd for C15H15NO3: C, 70.02; H, 5.88;
N, 5.44. Found: C, 70.23; H, 5.90; N, 5.60.
To a solution or suspension of appropriate base (NaH,
t-BuOK, LiH or KH, 3 mmol) in solvent (DME or t-BuOH,
5 mL) was added a solution of the appropriate alcohols 3–7
(1.5 mmol) in solvent (5 mL). The resulting mixture was
heated (80 8C) for 4–72 h. After cooling to room tempera-
ture, the reaction was hydrolysed with H2O and extracted
with AcOEt. The organic layer was dried (MgSO4) and
concentrated in vacuo to give a residue which was purified
by column chromatography (eluent: MeOH/CH2Cl2,
gradient: 0.2:9.8 to 1:9) to afford dioxinopyridines 8–12
(see Tables 1–4). Using as starting materials the chloro-
derivatives 4b, 6b and 7b (Table 3, entry 1, 5 and 9) only the
isomers 9A, 10A and 11A are obtained. The structure and
the ratio of 9B, 10B and 11B were deduced from the spectral
data of their isomeric mixture.
4.6.5. Benzyl-(2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-
ylmethyl)-methylamine 10A. Oil; IR (film) n 1190
1
(C–O–C) cm21; H NMR (CDCl3) d 2.32 (s, 3H, CH3);
2.70–2.80 (m, 2H, Ph-CH2–N); 3.47 (d, 1H, J¼13.1 Hz,
Ph-CH2–NH–CH2); 3.60 (d, 1H, J¼13.1 Hz, Ph-CH2–
NH–CH2); 3.84 (dd, 1H, J¼7.7, 11.5 Hz, O–CH2–CH);

S. Lazar et al. / Tetrahedron 60 (2004) 6461–6473
6471
4.27 (dd, 1H, J¼2.4, 11.5 Hz, O–CH2–CH); 4.39–4.50 (m,
1H, O–CH2–CH); 6.77 (dd, 1H, J¼4.8, 7.9 Hz, Hb,); 7.10
(dd, 1H, J¼1.6, 7.8 Hz, Hg); 7.21–7.29 (m, 5H, Har);
7.77 (dd, 1H, J¼1.6, 4.8 Hz, Ha); 13C NMR (CDCl3) d 43.4;
56.8; 62.9; 66.5; 72.6; 118.2; 124.4; 127.1; 128.2; 128.8;
138.6; 139.0; 139.8; 150.8; MS (CI) m/z 271 (Mþ1); Anal.
calcd for C16H18N2O2: C, 71.09; H, 6.71; N, 10.36. Found:
C, 71.21; H, 6.80; N, 10.28.
4.6.10. 2-Azidomethyl-2,3-dihydro[1,4]dioxino[2,3-
b]pyridine 12B. Oil; IR (film) n 2108 (N3), 1277 (C–O–
C) cm21; 1H NMR (CDCl3) d 3.47 (d, 2H, J¼5.3 Hz, CH–
CH2–N3), 4.14 (dd, 1H, J¼6.7, 11.1 Hz, O–CH2–CH),
4.28–4.29 (m, 1H, O–CH2–CH), 4.34 (dd, 1H, J¼2.0,
11.1 Hz, O–CH2–CH), 6.79 (dd, 1H, J¼4.7, 7.8 Hz, Hb),
7.13 (dd, 1H, J¼1.6, 7.8 Hz, Hg), 7.73 (dd, 1H, J¼1.6,
4.7 Hz, Ha); 13C NMR (CDCl3) d 50.2, 65.6, 71.6, 118.7,
124.9, 138.0, 140.0, 150.2; MS (CI) m/z 193 (Mþ1); Anal.
calcd for C8H8N4O2: C, 50.00; H, 4.20; N, 29.15. Found: C,
50.08; H, 4.17; N, 29.20.
4.6.6. Benzyl-(2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-
ylmethyl)-methylamine 10B. IR (film) n 1190 (C–O–C)
cm21; 1H NMR (CDCl3) d 2.34 (s, 3H, CH3); 2.60–2.68 (m,
2H, Ph-CH2–N); 3.49 (d, 1H, J¼13.1 Hz, Ph-CH2–NH–
CH2); 3.60 (d, 1H, J¼13.1 Hz, Ph-CH2–NH–CH2); 4.04
(dd, 1H, J¼7.7, 11.5 Hz, O–CH2–CH); 4.27 (dd, 1H,
J¼2.4, 11.5 Hz, O–CH2–CH); 4.37–4.50 (m, 1H,
O–CH2–CH); 6.76 (dd, 1H, J¼4.8, 7.9 Hz, Hb,); 7.11
(dd, 1H, J¼1.6, 7.8 Hz, Hg); 7.22–7.30 (m, 5H, Har); 7.79
(dd, 1H, J¼1.6, 4.8 Hz, Ha); 13C NMR (CDCl3) d 43.5;
56.9; 63.1; 67.6; 71.5; 118.5; 124.8; 127.4; 128.4; 129.0;
138.5; 138.9; 139.8; 151.1; MS (CI) m/z 271 (Mþ1); Anal.
calcd for C16H18N2O2: C, 71.09; H, 6.71; N, 10.36. Found:
C, 71.34; H, 6.62; N, 10.30.
4.7. General procedure for the preparation of the
compounds 13–15
A solution of dioxinopyridines 9, 10 or 11 (0.68 mmol) in
MeOH (25 mL) with a few drops of HCl was shaken with
Pd/C (10%, 20 mg) under hydrogen atmosphere. When the
reaction was complete, the catalyst was removed by
filtration and the combined filtrate was concentrated in
vacuo to give 13, 14 or 15 (82–88%).
(2,3-Dihydro[1,4]dioxino[2,3-b]pyridin-3 and 2-yl)-metha-
nol (13A, 13B), (2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3
and 2-ylmethyl)-methylamine (14A, 14B), (2,3-
dihydro[1,4]dioxino[2,3-b]pyridin-3 and 2-yl)-methylamine
(15A, 15B). The analytical data of 13A, 13B, 14A, 14B,
15A and 15B were in accordance with the values described
in the literature 22.
4.6.7. Benzyl-(2,3-dihydro[1,4]dioxino[2,3-b]pyridin-3-
ylmethyl)-amine 11A. Oil; IR (film) n 1190 (C–O–C)
cm21; 1H NMR (CDCl3) d 1.83 (broad s, 1H, NH), 2.94 (d,
2H, J¼4.5 Hz, Ph-CH2–NH–CH2), 3.83 (s, 2H, Ph-CH2–
N), 4.05 (dd, 1H, J¼8.1, 11.5 Hz, O–CH2–CH), 4.26 (dd,
1H, J¼2.3, 11.5 Hz, O–CH2–CH), 4.40–4.51 (m, 1H,
O–CH2–CH), 6.84 (dd, 1H, J¼4.9, 7.9 Hz, Hb), 7.16 (dd,
1H, J¼1.7, 7.9 Hz, Hg), 7.25–7.38 (m, 5H, Har), 7.80 (dd,
1H, J¼1.7, 4.9 Hz, Ha); 13C NMR (CDCl3) d 48.9, 54.0,
67.2, 72.7, 118.5, 124.9, 127.3, 128.2, 128.6, 138.9, 139.9,
140.0, 151.0; MS (CI) m/z 257 (Mþ1); Anal. calcd for
C15H16N2O2: C, 70.29; H, 6.29; N, 10.93. Found: C, 70.11;
H, 6.30; N, 10.78.
4.8. Preparation of the compounds 17 from 13
p-Toluenesulfonyl chloride (2.85 g, 15.00 mmol) was added
to a solutionof alcohol 13A (or 13B) (10.00 mmol) in pyridine
(20 mL) at 0 8C. The reaction mixture was stirred for 48 h then
the solvent was removed under reduced pressure. The residue
was subjected to silica gel chromatography (eluent: CH2Cl2)
to give 16A (87%) (or 16B, 85%).
4.6.8. Benzyl-(2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-
ylmethyl)-amine 11B. IR (film) n 1200 (C–O–C) cm21
;
4.8.1. 2,3-Dihydro[1,4]dioxino[2,3-b]pyridin-3-ylmethyl-
4-methylbenzenesulfonate 16A. Oil; IR (film) n 1350 and
1H NMR (CDCl3) d 1.79 (broad s, 1H, NH), 2.97 (d, 2H,
J¼4.7 Hz, Ph-CH2–NH–CH2), 4.03 (s, 2H, Ph-CH2–N),
4.13 (dd, 1H, J¼7.9, 11.6 Hz, O–CH2–CH), 4.41 (dd, 1H,
J¼2.3, 11.6 Hz, O–CH2–CH), 4.45–4.56 (m, 1H,
O–CH2–CH), 6.87 (dd, 1H, J¼4.8, 7.8 Hz, Hb), 7.20 (dd,
1H, J¼1.7, 7.9 Hz, Hg), 7.29–7.42 (m, 5H, Har), 7.81 (dd,
1H, J¼1.6, 4.9 Hz, Ha); 13C NMR (CDCl3) d 49.8, 54.0,
66.3, 72.8, 118.7, 125.2, 127.4, 128.4, 128.9, 138.6, 139.8,
139.9, 151.1; MS (CI) m/z 257 (Mþ1); Anal. calcd for
C15H16N2O2: C, 70.29; H, 6.29; N, 10.93. Found: C, 70.15;
H, 6.37; N, 10.83.
1
1110 (SO2) cm21; H NMR (CDCl3) d 2.45 (s, 3H, CH3),
4.07 (dd, 1H, J¼6.7, 11.6 Hz, O–CH2–CH), 4.17–4.40 (m,
3H, O–CH2–CH, CH–CH2–O–Ts), 4.51–4.65 (m, 1H,
O–CH2–CH), 6.87 (dd, 1H, J¼5.0, 7.8 Hz, Hb), 7.18 (dd,
1H, J¼1.6, 7.8 Hz, Hg), 7.31–7.45 (m, 2H, Har), 7.72–7.93
(m, 3H, Ha, Har); 13C NMR (CDCl3) d 21.7, 64.2, 66.7, 71.3,
118.9, 125.1, 128.1, 130.1, 132.1, 138.6, 140.4, 145.5,
150.0; MS (CI) m/z 322 (Mþ1); Anal. calcd for
C15H15NO5S: C, 56.06; H, 4.70; N, 4.36. Found: C, 56.15;
H, 4.85; N, 4.28.
4.6.9. 3-Azidomethyl-2,3-dihydro[1,4]dioxino[2,3-
b]pyridine 12A. Oil; IR (film) n 2108 (N3), 1277 (C–O–
4.8.2. 2,3-Dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl-
4-methylbenzenesulfonate 16B. Oil; IR (film) n 1345 and
1
C) cm21
;
1H NMR (CDCl3) d 3.59 (d, 2H, J¼5.6 Hz,
1110 (SO2) cm21; H NMR (CDCl3) d 2.44 (s, 3H, CH3),
CH–CH2–N3), 4.02 (dd, 1H, J¼7.3, 11.6 Hz, O–CH2–
CH), 4.23 (dd, 1H, J¼2.5, 11.6 Hz, O–CH2–CH),
4.39–4.48 (m, 1H, O–CH2–CH), 6.84 (dd, 1H, J¼4.7,
7.8 Hz, Hb), 7.15 (dd, 1H, J¼1.7, 7.8 Hz, Hg), 7.79 (dd, 1H,
J¼1.7, 4.7 Hz, Ha); 13C NMR (CDCl3) d 50.5, 65.0, 72.6,
118.8, 124.9, 138.7, 140.3, 150.2; MS (CI) m/z 193 (Mþ1);
Anal. calcd for C8H8N4O2: C, 50.00; H, 4.20; N, 29.15.
Found: C, 50.12; H, 4.35; N, 29.08.
4.14–4.29 (m, 3H, O–CH2–CH), 4.37–4.47 (m, 2H, CH–
CH2–O–Ts), 6.86 (dd, 1H, J¼4.9, 7.9 Hz, Hb), 7.10 (dd,
1H, J¼1.7, 7.9 Hz, Hg), 7.36 (d, 2H, J¼8.1 Hz, Har), 7.75–
7.84 (m, 3H, Ha, Har); 13C NMR (CDCl3) d 21.6, 64.8, 66.9,
70.1, 118.8, 125.0, 127.9, 130.0, 132.1, 137.9, 140.1, 145.4,
150.1; MS (CI) m/z 322 (Mþ1); Anal. calcd for
C15H15NO5S: C, 56.06; H, 4.70; N, 4.36. Found: C, 56.19;
H, 4.55; N, 4.29.

6472
S. Lazar et al. / Tetrahedron 60 (2004) 6461–6473
The compound 16A (or 16B) (0.38 mmol) was heated at
130 8C for 8 h in a sealed tube with a mixture of
methylamine (2 M, 5 mL) and DMF (5 mL). Addition of
H2O, extraction by CH2Cl2, drying over MgSO4 and
removal of the solvent afforded a crude product, which
purified by column chromatography (eluent: MeOH/
CH2Cl2, 1:9), yielding 73% of the N-methylamine 14A (or
63% of 14B). The analytical data were identical with those
reported above.
15A or 15B (9.20 mmol) in ethylene glycol (40 mL). The
reaction mixture was stirred at 110 8C for 1.5 h. The
solution was cooled 25 8C and concentrated under reduced
pressure. The residue was taken in CH2Cl2 and washed with
H2O. The organic layer was dried (MgSO4) and the solvent
was removed. The residue was subjected to flash silica gel
chromatography (eluent: MeOH/CH2Cl2, 1:9) to afford the
product 8A in 69% yield (8B in 65% yield). The analytical
data were identical with those reported above.
Under similar sulfonation reaction conditions described for
13, the resulting amines 14A and 14B were converted into
their sulfonated derivatives 17A and 17B in good yields 90
and 88%, respectively.
Acknowledgements
The authors thank Dr. J. Willems from Janssen Pharma-
ceutica for his significant remark concerning our article
cited in the Ref. 22.
4.8.3. N-(2,3-Dihydro[1,4]dioxino[2,3-b]pyridin-3-
ylmethyl)-4,N-dimethylbenzenesulfonamide 17A. Mp
135–136 8C; IR (KBr) n 1463 (CH3), 1335 (SO2), 1278
and 1163 (C–O–C) cm21; 1H NMR (CDCl3) d 2.44 (s, 3H,
CH3), 2.92 (s, 3H, CH3), 3.33 (dd, 1H, J¼4.8, 14.6 Hz,
O–CH2–CH), 3.42 (dd, 1H, J¼5.6, 14.6 Hz, O–CH2–CH),
4.15 (dd, 1H, J¼7.3, 11.7 Hz, CH–CH2–N–CH3), 4.45
(dd, 1H, J¼7.3, 11.7 Hz, CH–CH2–N–CH3), 4.50–4.61
(m, 1H, O–CH2–CH), 6.88 (dd, 1H, J¼4.6, 7.8 Hz, Hb),
7.22 (dd, 1H, J¼1.6, 7.8 Hz, Hg), 7.35 (d, 2H, J¼8.2 Hz,
Har), 7.69 (d, 2H, J¼8.2 Hz, Har), 7.82 (dd, 1H, J¼1.5,
4.6 Hz, Ha); 13C NMR (CDCl3) d 21.7, 37.6, 50.5, 65.7,
73.3, 118.8, 125.0, 127.5, 130.0, 134.0, 139.0, 140.2, 144.0,
150.5; MS (CI) m/z 335 (Mþ1); Anal. calcd for
C16H18N2O4S: C, 57.47; H, 5.43; N, 8.38. Found: C,
57.35; H, 5.39; N, 8.28.
References and notes
1. Guillaumet, G.; 1st ed.; Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F.
V., Eds.; Pergamon: Oxford, 1996; Vol. 6, p 447.
2. Stillings, M.; Chapleo, C. B.; Butler, R. C. M.; Davis, J. A.;
England, C. D.; Myers, M.; Tweddle, N.; Welbourn, A. P.;
Doxey, J. C.; Smith, C. F. C. J. Med. Chem. 1985, 28, 1054.
3. Campbell, S.; Davey, M. J.; Hardstone, J. D.; Lewis, B. N.;
Palmer, M. J. J. Med. Chem. 1987, 30, 49.
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5. Khouili, M.; Guillaumet, G.; Coudert, G.; Pujol, M. D. Il
Farmaco 1996, 51, 175.
4.8.4. N-(2,3-Dihydro[1,4]dioxino[2,3-b]pyridin-2-
ylmethyl)-4,N-dimethylbenzenesulfonamide 17B. Mp
99–100 8C; IR (KBr) n 1474 (CH3), 1397 (SO2), 1285
and 1153 (C–O–C) cm21; 1H NMR (CDCl3) d 2.39 (s, 3H,
CH3), 2.85 (s, 3H, CH3), 3.26 (d, 2H, J¼5.6 Hz, CH–CH2–
N–CH3), 4.23 (dd, 1H, J¼6.9, 11.6 Hz, O–CH2–CH),
4.32–4.44 (m, 1H, O–CH2–CH), 4.50 (dd, 1H, J¼2.2,
11.6 Hz, O–CH2–CH), 6.83 (dd, 1H, J¼4.7, 7.9 Hz, Hb),
7.11 (dd, 1H, J¼1.6, 7.9 Hz, Hg), 7.25–7.35 (m, 2H, Har),
7.60–7.70 (m, 2H, Har), 7.78 (dd, 1H, J¼1.6, 4.67 Hz, Ha);
13C NMR (CDCl3) d 21.5, 37.4, 50.2, 66.4, 72.0, 118.7,
125.0, 127.4, 129.9, 134.0, 138.3, 140.1, 143.9, 150.6; MS
(CI) m/z 335 (Mþ1); Anal. calcd for C16H18N2O4S: C,
57.47; H, 5.43; N, 8.38. Found: C, 57.38; H, 5.34; N, 8.47.
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4.9. Preparation of the amines 15 from 12
Azide 12A (or 12B) (2.6 mmol) in EtOH (16 mL) was
stirred with Lindlar palladium (0.08 mmol) in Parr
apparatus under hydrogen pressure (30 psi). After 4 h,
palladium was filtered and washed with EtOH. The solvent
was evaporated and a column chromatography (eluent:
MeOH/CH2Cl2, 1:9) afforded the product 15A as an oil in
99% yield (15B in 95% yield). The analytical data were
identical with those reported above.
12. Birch, A. M.; Bradley, P. A.; Gill, J. C.; Kerrigan, F.;
Needham, P. L. J. Med. Chem. 1999, 42, 3342, and references
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13. Munk, S.; Harcourt, D. A.; Arasasingham, P. N.; Burke, J. A.;
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´
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4.10. Preparation of the compounds 8 from 15
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N,N-Bis(2-chloroethyl)aniline (1.0 g, 4.60 mmol), sodium
hydrogen carbonate (1.16 g, 13.80 mmol), sodium iodide
(1.38 g, 9.20 mmol) were added to a solution of the amine

S. Lazar et al. / Tetrahedron 60 (2004) 6461–6473
6473
17. Fukuyama, Y.; Hasegawa, T.; Toda, M.; Kodama, M.;
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Table 1. Conditions of cyclization reactions of alcohols 2–5
Entry
Y
Base/solvent
T (8C)/t (h) Yield % Ratio
A/B
5
CH2NHCH2Ph NaH/DME 80/12
t-BuOK/t-BuOH 80/12
90
89
45/55
30/70