Novel analogues of 3-substituted-2,3-dihydro-1,4-dioxino[2,3-b]pyridines: Modifications in the dioxane ring

Article abstract of DOI:10.1016/j.tetlet.2003.09.145

The synthesis of a series of novel analogues of the 3-substituted-2,3- dihydro-1,4-dioxino[2,3-b]pyridine core, modified in the non-aromatic ring, is described. Due to the presence of a versatile hydroxymethyl group in their structure, these novel scaffol

Full text of DOI:10.1016/j.tetlet.2003.09.145

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8545–8548
Novel analogues of
3-substituted-2,3-dihydro-1,4-dioxino[2,3-b]pyridines:
modifications in the dioxane ring
Jose´ M. Bartolome´a,a,* Jesu´s Alca´zar,a J. Ignacio Andre´s,a Marcel De Bruyn,b Javier Ferna´ndez,a
Encarna Matesanza and Kristof Van Emelenb
aJohnson & Johnson Pharmaceutical Research & Development, a Division of Janssen-Cilag S.A.,
Medicinal Chemistry Dept., Jarama s/n, 45007 Toledo, Spain
bJohnson & Johnson Pharmaceutical Research & Development, a Division of Janssen Pharmaceutica N. V.,
Medicinal Chemistry Dept., Turnhoutseweg 30, B-2340 Beerse, Belgium
Received 22 July 2003; revised 29 August 2003; accepted 17 September 2003
Abstract—The synthesis of a series of novel analogues of the 3-substituted-2,3-dihydro-1,4-dioxino[2,3-b]pyridine core, modified
in the non-aromatic ring, is described. Due to the presence of a versatile hydroxymethyl group in their structure, these novel
scaffolds are attractive intermediates for the preparation of potential new therapeutic agents.
© 2003 Elsevier Ltd. All rights reserved.
Bioisosteric replacement of benzene by pyridine in com-
pounds containing the 2-substituted-2,3-dihydro-1,4-
benzodioxin core1 has yielded derivatives of biological
interest in diverse therapeutic areas such as CNS (5-
HT1A receptor agonists 12 and 23) and cardiovascular
diseases (calcium antagonist 34) (Fig. 1). These promis-
ing results have prompted interest in the area of 1,4-
dioxino-[2,3-b]pyridine analogues although described
modifications have been mainly focused on the pyridine
ring. Thus the synthetic routes to 1,4-dioxinopyridines
4,2,5 5,5,6 6,7 77 and to the 1,4-dioxino[2,3-d]pyrimidine
8,7 bearing a group on the non-aromatic ring amenable
to derivatization (FG), have been reported by Guil-
laumet and co-workers and by our group (Fig. 1).
In spite of these interesting preliminary findings, to our
knowledge, the only potentially derivatizable analogues
of the 3-substituted-2,3-dihydro-1,4-dioxino[2,3-b]pyri-
dine core modified in the 1,4-dioxane ring reported in
the literature are systems 98 and 109 (Fig. 2).
Figure 1.
* Corresponding author. Tel.: +34 925 245 750; fax: +34 925 245 771; e-mail: jbartolo@prdes.jnj.com
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.145

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J. M. Bartolome´a et al. / Tetrahedron Letters 44 (2003) 8545–8548
1
pyridine 13 as confirmed by its H NMR and LC/MS
data.13
The procedure followed to replace the oxygen atom at
position 4 of the 1,4-dioxane ring by a carbon is shown
in Scheme 2. Key intermediate 17 was prepared from
3-hydroxypyridine-2-carboxaldehyde 1414 following a
one-pot procedure previously described for salicylalde-
hyde.15 This procedure involved Michael addition of
the sodium salt of 14 to ethyl 2-diethylphosphonoacryl-
ate 15,15 at room temperature, furnishing intermediate
phosphonate anion 16.15 Subsequent heating of the
reaction mixture at reflux temperature promoted
intramolecular Wadswoth–Emmons cyclization of 16 to
the corresponding bicyclic system 17, obtained in low
yield but easily purified by standard chromatographic
procedures.16 Finally, sequential ester group reduction
of 17, by treatment with NaBH4, to the corresponding
alcohol and palladium catalyzed double bond hydro-
genation afforded the desired 3-hydroxymethyl-3,4-
dihydro-2H-pyrano[3,2-b]pyridine 18 according to its
spectroscopical and analytical data.17
Figure 2.
Herein we report on the most relevant results of our
work in this area included in the development of one of
our Drug Discovery Programs. Synthetic routes to four
novel analogues of the 3-substituted-2,3-dihydro-1,4-
dioxino[2,3-b]pyridine nucleus modified in the oxy-
genated ring are described. The versatile hydroxymethyl
group present in the structure of these scaffolds makes
them attractive intermediates for the synthesis of novel
potential bioactive compounds.
The first targeted modification was the constraint of the
1,4-dioxane ring to a five-membered 1,3-dioxolane ring.
The synthesis was initiated using commercially avail-
able 2,3-dihydroxypyridine 11 as starting material
(Scheme 1). Thus, reaction of 11 with methyl
dichloroacetate in DMF in the presence of 2.5 equiva-
lents of NaH as base afforded, in low yield,10 the
1,3-dioxolo[4,5-b]pyridine 12.11 Reduction of the ester
group of 12 using LiAlH4 yielded, after 1 h of reac-
tion,12 the expected 2-hydroxymethyl-1,3-dioxolo[4,5-b]-
Once the synthesis of scaffolds 13 and 18 had been
achieved our efforts were focused on the replacement of
the oxygen atoms of the 1,4-dioxane ring by other
heteroatoms. In this sense, chemical exploration of
various synthetic routes towards these modifications is
represented in Schemes 3 and 4.
Scheme 1.
Scheme 2.
Scheme 3.
Scheme 4.

J. M. Bartolome´a et al. / Tetrahedron Letters 44 (2003) 8545–8548
8547
For the substitution of the oxygen atom at position 4
by sulphur we used the corresponding 2-chloropyridine
derivative 19 as starting material, prepared according to
a previously described procedure.18 The 2,3-dihydro-
[1,4]oxathiino[2,3-b]pyridine bicyclic core of 21 was
prepared in one step from 19 by reaction with Lawes-
son’s reagent in refluxing toluene. This step involved
sequential conversion of the hydroxy group of 19 into
the corresponding thiol intermediate that was not
detected in the reaction media, followed by in situ
intramolecular cyclization of 20, furnishing system 21.19
The last step of the synthesis was the debenzylation of
21, using FeCl320 affording the corresponding 3-hydroxy-
Tetrahedron Lett. 2000, 41, 6079–6082; (c) Ward, R. S.
Nat. Prod. Rep. 1999, 16, 75–96; (d) Bolognesi, M. L.;
Budriesi, R.; Cavalli, A.; Chiarini, A.; Gotti, R.; Leon-
ardi, A.; Minarini, A.; Poggesi, E.; Recanatini, M.;
Rosini, M.; Tumiatti, V.; Melchiorre, C. J. Med. Chem.
1999, 42, 4214–4224; (d) Guillaumet, G. In Comprehen-
sive Heterocyclic Chemistry II, 1st ed.; Katrizky, A. R.;
Rees, C. W.; Scriven, E. F. V., Eds.; Pergamon: Oxford,
1996; Vol. 6, pp. 447–463.
2. Benarab, A.; Guillaumet, G. Heterocycles 1993, 36, 2327–
2333.
3. Comoy, C.; Benarab, A.; Monteil, A.; Leinot, M.; Mass-
ingham, R.; Guillaumet, G. Med. Chem. Res. 1996, 392–
399.
4. Sa´nchez, I.; Pujol, M. D.; Guillaumet, G.; Massingham,
R.; Monteil, A.; Dureng, G.; Winslow, E. Sci. Pharm.
2000, 68, 159–164.
methyl-2,3-dihydro[1,4]-oxathiino[2,3-b]pyridine
22
(Scheme 3).21 The structure of this compound was
confirmed by its 1H NMR spectrum and analytical
data.21
5. Soukri, M.; Lazar, S.; Akssira, M.; Guillaumet, G. Org.
Lett. 2000, 2, 1557–1560.
6. Benarab, A.; Commoy, C.; Guillaumet, G. Heterocycles
1994, 38, 1641–1650.
7. Matesanz, E.; Alca´zar, J.; Andre´s, J. I.; Bartolome´, J. M.;
De Bruyn, M.; Ferna´ndez, J.; Van Emelen, K. Tetra-
hedron Lett. 2003, 44, 2275–2277.
8. Dieter, A.; Heine, G.; Schohe-Loop, R.; Glaser, T.; De
Vry, J. M. V. EP 519291, 1992; Chem. Abstr. 1993, 118,
234051.
9. Arrault, A.; Touzeau, F.; Guillaumet, G.; Le´ger, J. M.;
Jarrry, C.; Me´rour, J. Y. Tetrahedron 2002, 58, 8145–
8152.
10. When the reaction was tried using NaH in DMF at room
temperature or sodium methoxide in MeOH both, at
room temperature and under reflux only starting material
was recovered unaltered.
11. In spite of the low yield, 12 was obtained in pure form
after standard flash column chromatography over silica
gel eluting sequentially with CH2Cl2, CH2Cl2/acetone (25/
1) and CH2Cl2/MeOH (25/1).
12. Longer reaction times afforded mainly decomposition.
13. Analytical data for 13: syrup; 1H NMR (400 MHz,
CDCl3, 25°C): l 7.63 (dd, J=5.4 and 1.4 Hz, 1H, Ar),
6.95 (dd, J=7.6 and 1.4 Hz, 1H, Ar), 6.74 (dd, J=7.6
Finally, for the last modification reported, introduction
of an amino methyl group at position 1, the synthetic
scheme starts with the alkylation of 2-chloro-3-methyl-
aminopyridine 2322 with 2-(benzyloxymethyl)oxirane, in
the presence of LDA as base,23 yielding the correspond-
ing alcohol 24. Intramolecular base-promoted cycliza-
tion of 24, using NaH in refluxing 1,2-dimethoxyethane
(DME) furnished compound 25 which already pos-
sesses the desired bicyclic nucleus. Finally, O-debenzy-
lation of 25 using FeCl3 led to the corresponding
3-hydroxymethyl-1-methyl-2,3-dihydro-1H-
[1,4]oxazin[2,3-b]pyridine system 26 in good yield
(Scheme 4). Confirmation of the structure of 26 was
obtained by analysis of its NMR data.24
In summary, we have developed new synthetic schemes
that have allowed the straightforward preparation of
close analogues of the 2,3-dihydro-1,4-dioxino[2,3-b]-
pyridine system containing a modified dioxane ring.
These previously unattainable scaffolds have a deriva-
tizable group (hydroxymethyl) on the non-aromatic
ring that could allow their introduction into more
complex systems. These new bicyclic cores may be
considered as promising intermediates for the synthesis
of novel potential therapeutic agents. Further deriva-
tization of the reported systems is ongoing and will be
described in due course.
and 5.4 Hz, 1H, Ar), 6.28 (t, J=4.3 Hz, 1H, CH
6
), 3.77
6 ); MS
(d, J=4.3 Hz, 2H, CH2OH), 1.93–1.62 (bs, 1H, OH
6
(electrospray+) C7H7NO3: MW 153; found (M+H)+: 154.
14. Demerseman, P.; Kiffer, D.; Debussche, L.; Lion, C.;
Royer, R.; Sentenac-Roumanou, H. Eur. J. Med. Chem.
1988, 23, 63–68.
Acknowledgements
15. Kleshick, W. A.; Heathcock, C. H. J. Org. Chem. 1978,
43, 1256–1259.
The valuable collaboration and help of Mr. Jose´
Manuel Alonso, Ms. Valle Ancos, Mr. Luis Font, Dr.
Antonio Go´mez, Dr. Laura Iturrino and Ms. Carmen
Nieto during the development of the work presented in
this communication are gratefully acknowledged.
16. Flash column chromatography over silica gel eluting first
with CH2Cl2 and then with CH2Cl2/acetone (9/1 and 4/1).
17. Analytical data for 18: foam; 1H NMR (400 MHz,
CDCl3, 25°C): l 8.12 (dd, J=4.5 and 1.5 Hz, 1H, Ar),
7.09 (dd, J=8.2 and 1.5 Hz, 1H, Ar), 7.04 (dd, J=8.2
and 4.5 Hz, 1H, Ar), 4.30 (d, J=10.7 Hz, 1H, OCH2
3.89 (dd, J=10.7 and 7.2 Hz, 1H, OCH2), 3.13–3.07 (m,
2H, CH2OH), 3.04 (dd, J=17.2 and 3.3 Hz, 1H,
CH2CH), 2.68 (dd, J=17.2 and 7.4 Hz, 1H, CH2CH),
); MS
6 ),
6
References
6
6
6
1. For recent reports involving 2,3-dihydro-1,4-benzodioxin
derivatives, see: (a) Czompa, A.; Dinya, Z.; Antus, S.;
Varga, Z. Arch. Pharm. 2000, 333, 175–180; (b) Gu, W.
X.; Jing, X. B.; Pan, X. F.; Chan, A. S. C.; Yang, T. K.
2.39–2.32 (m, 1H, CH6 ), 1.87–1.57 (bs, 1H, OH6
(electrospray+) C9H11NO2: MW 165; found (M+H)+:
166.

8548
J. M. Bartolome´a et al. / Tetrahedron Letters 44 (2003) 8545–8548
18. Benarab, A.; Poirot, P.; Guillaumet, G. Heterocycles
1993, 36, 1589–1599.
3.68 (m, 2H, CH6 2OH), 3.65–3.59 (m, 1H, CH6 ), 1.98–1.67
(bs, 1H, OH6 ); MS (electrospray+) C8H9NO2S: MW 183;
found (M+H)+: 184.
19. Intermediate 20 was obtained after two consecutive flash
column chromatographies over silica gel. The first one,
eluted with CH2Cl2/acetone (9/1), to remove Lawesson’s
reagent by-products obtained in the course of the reac-
tion and the second one, eluted with hexane/acetone
(9/1), to obtain the pure compound.
22. Proudfoot, J. R. Biorg. Med. Chem. 1995, 5, 163–166.
23. When the epoxide opening was tried in the absence of
base or using weaker bases, such as Cs2CO3 or NaH, no
reaction took place.
24. Analytical data for 26: syrup; 1H NMR (400 MHz,
CDCl3, 25°C): l 7.58 (dd, J=4.7 and 1.7, 1H, Ar), 6.89
(dd, J=7.8 and 1.7 Hz, 1H, Ar), 6.84 (dd, J=7.8 and 4.7
20. Park, M. H.; Takeda, R.; Nakanishi, K. Tetrahedron
Lett. 1987, 28, 3823–3824.
21. Analytical data for 22: foam; 1H NMR (400 MHz,
CDCl3, 25°C): l 8.07 (dd, J=4.6 and 1.5 Hz, 1H, Ar),
7.01 (dd, J=8.2 and 1.5 Hz, 1H, Ar), 6.93 (dd, J=8.2
and 4.6 Hz, 1H, Ar), 4.79 (dd, J=11.4 and 4.7 Hz, 1H,
Hz, 1H, Ar), 4.53–4.47 (m, 1H, CH
and 4.1 Hz, 1H, OCH2), 3.84 (dd, J=12.0 and 5.0 Hz,
1H, OCH2), 3.28–3.22 (m, 2H, CH2OH), 2.88 (s, 3H,
NCH3), 2.04–1.59 (bs, 1H, OH); MS (electrospray+)
C9H12N2O2: MW 180; found (M+H)+: 181.
6 ), 3.93 (dd, J=12.0
6
6
6
6
6
OCH6 2), 4.30 (dd, J=11.4 and 2.2 Hz, 1H, OCH6 2), 3.75–