Synthesis of novel aza analogues of 2-substituted-2,3-dihydro-1,4-benzodioxins as potential new scaffolds for drug discovery

Article abstract of DOI:10.1016/S0040-4039(03)00281-8

New synthesis approaches that have led to a series of novel aza analogues of the 2-substituted-2,3-dihydro-1,4-benzodioxin core, bearing versatile bromomethyl group on the non aromatic oxygenated ring, are described. According to their structures these novel scaffolds can be useful intermediates for the preparation of potential new therapeutic agents.

Full text of DOI:10.1016/S0040-4039(03)00281-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2275–2277
Synthesis of novel aza analogues of
2-substituted-2,3-dihydro-1,4-benzodioxins as potential new
scaffolds for drug discovery
Encarna Matesanz,a,* Jesu´s Alca´zar,a J. Ignacio Andre´s,a Jose M. Bartolome´,a Marcel De Bruyn,b
Javier Ferna´ndeza and Kristof Van Emelenb
aJohnson & Johnson Pharmaceutical Research & Development, a Division of Janssen-Cilag S.A.,
Medicinal Chemistry Department, Jarama s/n, 45007 Toledo, Spain
bJohnson & Johnson Pharmaceutical Research & Development, a Division of Janssen Pharmaceutica N.V.,
Medicinal Chemistry Department, Turnhoutseweg 30, B-2340 Beerse, Belgium
Received 17 December 2002; accepted 30 January 2003
Abstract—New synthesis approaches that have led to a series of novel aza analogues of the 2-substituted-2,3-dihydro-1,4-benzo-
dioxin core, bearing versatile bromomethyl group on the non aromatic oxygenated ring, are described. According to their
structures these novel scaffolds can be useful intermediates for the preparation of potential new therapeutic agents. © 2003
Elsevier Science Ltd. All rights reserved.
The 2,3-dihydro-1,4-benzodioxin core is present in the
structure of several biologically interesting com-
pounds.1 Bioisosteric replacement of benzene by pyri-
dine has proved to be one of the most useful tools for
medicinal chemists over the years.2 This replacement
can often be done without any significant influence on
the biological activity despite the different electronic
distribution and the additional basic character of the
pyridine ring.2 For instance, Guillaumet and co-work-
ers have demonstrated the generality of this approach
by synthesizing the 1,4-dioxino[2,3-b]pyridine deriva-
tives 3,3 44 and 55 as bioanalogues of MDL 72832 1
(5-HT1A receptor agonist) and 2 (calcium antagonist)
respectively with maintenance of the primary biologi-
cal activity (Fig. 1).
In spite of these findings, and up to our knowledge,
the only aza analogues of the 2,3-dihydro-1,4-benzodi-
oxin skeleton, bearing a functional group amenable to
derivatization (FG) on the non-aromatic ring, previ-
ously reported in the literature are 2,3-dihydro-1,4-
dioxino[2,3-b]pyridines of general formulas 63,6 and
76,7 (Fig. 1).
As part of a Drug Discovery Program we were inter-
ested in the preparation of this kind of heterocycles as
Figure 1.
Keywords: pyridine; heterocycles; 1,4-benzodioxin; 1,4-pyridodioxin; novel scaffolds.
* Corresponding author. Tel.: +34 925 245 750; fax: +34 925 245 771; e-mail: ematesan@prdes.jnj.com
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00281-8

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E. Matesanz et al. / Tetrahedron Letters 44 (2003) 2275–2277
intermediates for the synthesis of more complex sys-
tems. In this communication we now report on the
synthesis strategies for the preparation of three novel
aza analogues of the 2,3-dihydro-1,4-benzodioxin core,
substituted with a bromomethyl group in the 1,4-diox-
ane ring. According to their structures, these novel
heterocycles can be useful intermediates for the synthe-
sis of novel bioactive compounds.
The starting material for the synthesis of 2-substituted-
2,3-dihydro-1,4-dioxino[2,3-c]pyridine 17 (Scheme 2)
was 4-chloro-3-hydroxypyridine 14.8 The corresponding
O-protected-3-allyloxy-4-hydroxypiridine intermediate
15 was prepared in two steps. Firstly, introduction of
the allyloxy group in 3 position by reaction of 14 with
allyl alcohol, under standard Mitsunobu conditions,12
yielded an intermediate which proved to be unstable
and had to be used immediately after its synthesis. In
second place, the introduction of the benzyloxy group
at the 4 position by aromatic nucleophilic substitution
with benzyl alcohol led to the desired compound 15.
Then, bromination of the double bond of 15 afforded
16, which was debenzylated using FeCl3 as deprotection
agent13 to give the corresponding hydroxy intermediate.
This compound was cyclized, without purification, in
refluxing EtOH using potassium sodium tartrate both
to remove iron complexes that interfere in the reaction
and as weak base, furnishing the expected system 17 as
confirmed by its NMR data.14
Within this general objective, our first efforts were
devoted to the synthesis of the two unreported regioiso-
meric 2,3-dihydro-1,4-dioxino[2,3-c]pyridine scaffolds.
In order to achieve this goal in both cases, and after
prospection of several possible synthetic pathways, we
followed the same strategy: to have a pyridine ring
substituted with a conveniently protected oxygen and
an allyloxy group in the appropriate positions (general
formulas 8 and 9) as starting point to generate the
desired bicyclic systems (Fig. 2).
For the preparation of the 3-substituted-2,3-dihydro-
1,4-dioxin[2,3-c]pyridine 13 (Scheme 1), we used as
starting material the MOM protected 4-chloro-3-
hydroxypyridine 10, prepared according to a previously
described procedure.8 The introduction of the allyloxy
group by aromatic nucleophilic substitution was carried
out by reaction of 10 with allyl alcohol in 1,2-
dimethoxyethane (DME) using NaH as base yielding
intermediate 11.9 Then, quantitative double bond
bromination of 11, by treatment with bromine in
CH2Cl2, and subsequent O-MOM deprotection in
acidic medium afforded compound 12. Finally, cycliza-
tion of 12 in refluxing EtOH, in absence of base or
using a weak base such as NaHCO3 furnished the
desired 3-bromomethyl-2,3-dihydro-1,4-dioxino[2,3-c]-
pyridine 13 in good yield.10 The regiochemistry of the
cyclization step was confirmed by analysis of the NMR
data of compound 13.11
After the obtention of systems 13 and 17, our work
focused on the introduction of a second nitrogen atom
in the aromatic ring of the 2-substituted-2,3-dihydro-
1,4-dioxino[2,3-c]pyridine skeleton, modification that
remained unpublished as well. In this sense, among all
the possible isomers, we considered the synthesis of the
corresponding 6,7-dihydro-1,4-dioxino[2,3-d]pyrimidine
core as the most feasible. For this purpose, we decided
to pursue a synthesis methodology similar to the one
previously used for the preparation of 13 and 17
(Scheme 3). Thus, dibrominated derivative 19 was pre-
pared, in moderate yield, by aromatic nucleophilic sub-
stitution of allyl alcohol on 5-bromopyrimidine 18
using NaH as base in absence of solvent,15 followed by
reaction with bromine in CH2Cl2. Subsequent oxidation
of the pyrimidine ring, using the CH3CO3H/H2SO4
system as oxidant,16 produced the pyrimidin-4-one 20
in good yield. Finally, intramolecular cyclization of 20
was achieved in refluxing EtOH in the presence of
NaHCO3 affording, according to its NMR data, 7-
bromomethyl-6,7-dihydro-1,4-dioxino[2,3-d]pyrimidine
21.17
Figure 2.
Scheme 1.
Scheme 2.

E. Matesanz et al. / Tetrahedron Letters 44 (2003) 2275–2277
2277
Scheme 3.
In conclusion, we have developed a new synthesis strat-
egy that has allowed us the straightforward preparation
of previously unattainable scaffolds, more precisely
close analogues of 2,3-dihydro-1,4-benzodioxin con-
taining nitrogen atoms on the phenyl ring. All these
novel systems have a derivatizable group (bromo-
methyl) on the oxygenated non-aromatic ring allowing
their introduction in more complex systems. According
to their structures these new bicyclic cores may be
promising intermediates in the synthesis of new poten-
tial therapeutic agents. Further derivatization of the
reported systems is on going and will be matter of
further publications.
7. Benarab, A.; Commoy, C.; Guillaumet, G. Heterocycles
1994, 38, 1641–1650.
8. Holladay, M. W.; Bai, H.; Yihong, L.; Nan-Horng, D.;
Jerome, F.; Ryther, K. B.; Wasicak, J. T.; Kincaid, J. F.;
He, Y.; Hettinger, A.-M.; Huang, P.; Anderson, D. J.;
Bannon, A. W.; Buckley, M. J.; Campbell, J. E.; Don-
nelly-Roberts, D. L.; Gunter, K. L.; Kim, D. J. B.;
Kuntzweiler, T. A.; Sullivan, J. P.; Decker, M. W.;
Arneric, S. P. Bioorg. Med. Chem. Lett. 1998, 8, 2797–
2802.
9. When DMF was used as solvent the allyloxygroup of 11
underwent spontaneous isomerization to the correspond-
ing enol–ether.
10. Cyclization step was tried in different conditions concern-
ing solvent, base and temperature: using either Et3N in
CHCl3 at reflux or NaH in DMF at room temperature, a
mixture of two compounds was obtained. In both cases
the desired product was the minor fraction while the
structure of the major fraction could not be determined.
11. Analytical data for 13: foam; 1H NMR (400 MHz,
CDCl3, 25°C): l 8.23 (s, 1H, Ar), 8.07 (d, J=5.4 Hz, 1H,
Acknowledgements
The authors wish to gratefully acknowledge Mr. Jose´
Manuel Alonso, Ms. Valle Ancos, Mr. Luis Font, Dr.
Antonio Go´mez, Dr. Laura Iturrino and Ms. Carmen
Nieto for their collaboration and help during the work
presented in this communication and Dr. Andre´s Tra-
banco for his help during the elaboration of this
manuscript.
Ar), 6.84 (d, J=5.4 Hz, 1H, Ar), 4.45 (m, 2H, CH
OCH2), 4.25 (dd, J=11.3 and 6.2 Hz, 1H, OCH2), 3.60
(dd, J=10.9 and 4.9 Hz, 1H, CH2Br), 3.52 (dd, J=10.9
and 7.4 Hz, 1H, CH2
Br); 13C NMR (75 MHz, CDCl3,
6 and
6
6
6
6
25°C): l 149.6 (C), 144.0 (CH), 140.6 (C), 140.1 (CH),
112.5 (CH), 72.2 (CH), 66.8 (CH2), 28.6 (CH2); MS
(electrospray +) C8H8BrNO2: Mw 230; found (M+H)+:
230.
References
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.
Tetrahedron Lett. 2000, 41, 6079–6082; (c) Ward, R. S.
Nat. Prod. Rep. 1999, 16, 75–96; (d) Bolognesi, M. L.;
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14. Analytical data for 17: syrup; 1H NMR (400 MHz,
CDCl3): l 8.26 (s, 1H, Ar), 8.02 (d, J=5.3 Hz, 1H, Ar),
6.87 (d, J=5.3 Hz, 1H, Ar), 4.46 (m, 1H, CH
J=11.8 and 2.3 Hz, 1H, OCH2), 4.17 (dd, J=11.8 and
6.2 Hz, 1H, OCH2), 3.52 (dd, J=11.0 and 5.1 Hz, 1H,
CH2Br), 3.47 (dd, J=11.0 and 7.3 Hz, 1H, CH2
Br); 13C
6 ), 4.37 (dd,
6
6
6
6
NMR (75 MHz, CDCl3, 25°C): l 148.8 (C), 143.3 (CH),
139.6 (C), 139.3 (CH), 112.2, 71.4 (CH), 65.6 (CH2), 27.9
(CH2); MS (electrospray +) C8H8BrNO2: Mw 230; found
(M+H)+: 230.
15. When the reaction was carried out on DMF or DMSO as
solvents the yield of the process dramatically decreased.
16. Kress, T. J. J. Org. Chem. 1985, 50, 3073–3076.
17. Analytical data for 21: foam; 1H NMR (400 MHz,
CDCl3): l 8.49 (s, 1H, Ar), 8.29 (s, 1H, Ar), 4.70 (m, 1H,
CH
J=11.9 and 6.4 Hz, 1H, OCH2
4.5 Hz, 1H, CH2Br), 3.55 (dd, J=11.0 and 8.1 Hz, 1H,
CH2
Br); 13C NMR (75 MHz, CDCl3, 25°C): l 154.2 (C),
6
), 4.48 (dd, J=11.9 and 2.4 Hz, 1H, OCH2
6 ), 4.25 (dd,
6
), 3.68 (dd, J=11.0 and
6
6
151.6 (CH), 144.7 (CH), 137.7 (C), 73.9 (CH), 65.4
(CH2), 27.3 (CH2); MS (electrospray +) C7H7BrN2O2:
Mw 231; found (M+H)+: 231.
6. Soukri, M.; Lazar, S.; Akssira, M.; Guillaumet, G. Org.
Lett. 2000, 2, 1557–1560.