Regioselective synthesis of 2,3-dihydrospiro[1,4]dioxino[2,3-b]pyridine derivatives

Article abstract of DOI:10.1016/j.tetlet.2010.06.061

2-Chloropyridines and an aryl bromide underwent palladium-catalyzed intramolecular C-O bond forming reactions to provide 2,3-dihydrospiro[1,4] dioxino[2,3-b]pyridine derivatives and a benzodioxin, regioselectively.

Full text of DOI:10.1016/j.tetlet.2010.06.061

Tetrahedron Letters 51 (2010) 4350–4353
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselective synthesis of 2,3-dihydrospiro[1,4]dioxino[2,3-b]pyridine
derivatives
*
Tony Kurissery A. , Santhosh Kumar Chittimalla, G. Abraham Rajkumar, Anjan Chakrabarti
AMRI Singapore Research Centre, 61 Science Park Road, #05-01 Galen, Science Park II, Singapore 117525, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 March 2010
Revised 2 June 2010
Accepted 11 June 2010
Available online 17 June 2010
2-Chloropyridines and an aryl bromide underwent palladium-catalyzed intramolecular C–O bond form-
ing reactions to provide 2,3-dihydrospiro[1,4]dioxino[2,3-b]pyridine derivatives and a benzodioxin,
regioselectively.
Ó 2010 Elsevier Ltd. All rights reserved.
2,3-Dihydro-1,4-benzodioxins occur widely as important struc-
tural units in natural products.1 They are utilized extensively in
suffers from a lack of regioselectivity and difficulties in the purifi-
cation and separation of regioisomeric mixtures (Scheme 1). The
only reported synthesis of spiro[1,4]benzodioxin 4 suffers from
harsh reaction conditions and low yields.10 In this Letter, we
describe a versatile approach for the regioselective synthesis of
3-substituted-2,3-dihydrospiro[1,4]dioxino[2,3-b]pyridine deriva-
tives and 2,20-spiro-1,4-benzodioxin via a palladium-catalyzed
SNAr reaction.
many pharmaceutically important compounds such as the
a-
adreno receptor antagonist WB 4101,2a serotonic 5-HT (5-hydro-
xytryptamine) receptor agonists,2b and as antipsychotic2c and
antigastric2d agents. 1,4-Benzodioxane derivatives also show high
potency against 5-lipoxygenases.2e
Replacement of a phenyl group by its bioisostere pyridine is an
established approach in drug discovery and is used widely in lead
optimization studies.3 2,3-Dihydro-1,4-dioxino[2,3-b]pyridines are
important structural motifs in many therapeutic agents with anti-
tumor activity4a such as the farnesyltransferase inhibitor 1a4b
(Fig. 1) and 5-HT1A receptor agonists.4c,d The 2,3-dihydro-1,4-diox-
ino[2,3-b]pyridine system is conceived as a 1,4-benzodioxane bio-
isostere and limited literature is available for the synthesis of such
compounds.5 Selective introduction of substituents on the pyridine
ring of 1,4-dioxino[2,3-b]pyridines has been studied previously.6
Further advancement in the synthesis of 2,3-dihydrospiro[1,4]-
dioxino[2,3-b]pyridine would be useful for the preparation of ther-
apeutically important compounds.7 The introduction of spirocycles
creates a rigid three dimensional arrangement and this type of con-
formational restriction strategy was utilized to develop selective
high affinity ligands for vesicular acetylcholine trasnsporters,8a
r1 receptor ligands,8b anti-ischemic activators of mitochondrial
ATP-sensitive potassium channels,8c potent non-peptidic inhibitors
of caspase-3,8d and the positive allosteric modulator8e 1b.
As a part of our drug discovery program we were interested in
the synthesis of 2,3-dihydrospiro[1,4]dioxino[2,3-b]pyridines 2
and 3. We were also interested in the preparation of 2,20-spiro-
1,4-benzodioxins 4 (Fig. 2) which are analogs of spirobenzofuran9a
and 3,4-dihydrospirobenzopyrans.9b
In our initial studies the reaction of commercially available
2-chloro-3-pyridinol (5a) with epoxide 6a11a in DMF and K2CO3
as base, afforded the tertiary alcohol 7a as the only product, as ex-
pected. The analytical data obtained was in agreement with the lit-
erature report.7
When the cyclization of 7a was performed according to the lit-
erature7 using various base/solvent combinations, either spirocycle
9a or an inseparable mixture of 8a and 9a in variable yields were
obtained (Scheme 1, Table 1). The obtained analytical data for 8a
and 9a were in agreement with the literature.7 The CH2–O group
of 9a (d 4.09) was shifted downfield after cyclization with respect
to 7a (d 3.88) but for 8a (d 3.92) the change in the chemical shift for
O
O
O
O
O
N
N
H
Cl
CH2CF3
N
N
O
N
N
1b
1a
Figure 1. 2,3-Dihydro-[1,4]dioxino[2,3-b]pyridine 1a and spiro[1,4]benzodioxin 1b
derivatives.
NH
O
O
O
O
The synthesis of compounds 2 and 3 has been previously
O
O
described in the literature,7 however, the reported synthesis of 2
N
N
NH
NH
2
3
4
* Corresponding author. Tel.: +65 6398 5502; fax: +65 6398 5511.
E-mail address: anthappan.tonyk@amriglobal.com (Tony K.A.).
Figure 2. Spirocyclic pyridinedioxins and benzodioxins.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.061

Tony K.A. et al. / Tetrahedron Letters 51 (2010) 4350–4353
4351
O
Cbz
N
Cbz
N
base
O
O
O
N
O
Bn
+
N
N
OH
O
N
N Bn
6a
Bn
Bn
8a
N
O
Cl
10
N
O
O
N
O
O
OH
Cl
conditions
O
N
+
Cbz
OH
11
12
base
N
N
Cl
O
O
7a
5a
Scheme 3. Intramolecular cyclization of 2-chloropyridine N-oxide 10.
N
9a
and 12 (Scheme 3, Table 1). Similar to 8a and 9a, the structures
for spirocycles 11 and 12 were also tentatively assigned based on
the chemical shift of the CH2–O group before and after cyclization.
For 12 the CH2–O group (d 4.24) was shifted downfield after cycli-
zation with respect to 10 (d 3.92) but for 11 (d 3.99) the change in
the chemical shift for CH2–O group was negligible. These observa-
tions indicated that any conventional SNAr reaction conditions on
substrates 7a and 10 would result in a regioisomeric spirocyclic
product mixture from the competitive reactions.
Transition metal catalyzed cross-coupling reactions have
emerged as a powerful tool for the formation of carbon–carbon15
and carbon-heteroatom16 (X = N, O, S) bonds. The importance of
metal-catalyzed reactions in the construction of heterocycles has
been reviewed.17 Buchwald reported the intramolecular coupling
reaction of various secondary and tertiary alcohols with aryl bro-
mides to provide oxygen-containing heterocycles via a palla-
dium-catalyzed C–O bond forming reaction.18 We were
interested to test the feasibility of the palladium-mediated intra-
molecular C–O bond forming conditions on 7a to furnish the de-
sired spiro-dioxinopyridines 8a, regioselectively. Following
treatment of tertiary alcohol 7a under Buchwald’s conditions18
(5 mol % Pd(OAc)2, BINAP, K2CO3, toluene) in a sealed tube, only
trace amounts of 8a were observed. However, when the catalyst
loading was increased from 5 to 10 mol %, the 3,30-spiro-1,4-diox-
ino[2,3-b]pyridine 8a was formed as a single regioisomer in good
yield (Table 2, entry 1). The obtained analytical data was in agree-
ment with the literature.7
In order to probe the scope and limitations of the synthesis, a
number of substituted chloropyridines, chloroquinolines and a
bromophenol were subjected to epoxide opening and subsequent
cyclization reactions. The requisite epoxides 6a–d11a and the 2-
chloro-3-pyridinols 5c and 5d and 3-hydroxy-2-chloroquinoline
(5b) were prepared by literature methods. Epoxides 6a–d were
readily obtained from corresponding piperidone and pyrrolidinone
by the literature procedures.11a,b 3-Hydroxy-2-chloroquinoline
(5b) was synthesized from 2-quinolone according to the procedure
reported by Quéguiner.19 5-Phenyl-3-chloro-2-pyridinol (5c) was
prepared from 3,5-dibromopyridine in four steps.20 6-Methyl-2-
chloro-3-pyridinol (5d) was prepared by chlorination of 6-
methyl-3-pyridinol using sodium hypochlorite.21
Scheme 1. Conventional SNAr reactions for the synthesis of spirocycles 8a and 9a.
Table 1
Conditions and product ratios for the cyclizations of 7a and 10
Substrate
Base/solvent
Temp (°C)
8a/9a
11/12
7a
7a
7a
7a
7a
10
10
10
10
10
10
NaH/DMF
80
80
70
70
80
70
70
0
0/100a
0/100a
65/35
50/50
0/100
KOt-Bu/t-BuOH
NaH/2-MeTHF
NaH/THF
KOH/toluene, 18-crown-6
Cs2CO3/DMF
Cs2CO3/acetone
NaH/DMF
NaH/DME
NaH/THF
NaH/2-MeTHF
0/100
0/100
0/100
0/100
35/65
50/50
25
25
25
a
A substantial amount of epoxide 6a was also isolated.
CH2–O group was negligible.7 A combination of strong base and po-
lar solvent always provided substantial amounts of epoxide 6a
(Scheme 2). The formation of 6a was suppressed when the reaction
was performed in toluene, a non-polar aprotic solvent. The best
product ratio for spirocyclic compounds 8a/9a was observed with
NaH/2-methyltetrahydrofuran (Table 1).
Product 9a is formed through a Smiles rearrangement interme-
diate (Int-2, Scheme 2) as is commonly observed7,12 with electron-
ically deactivated pyridines under strongly basic conditions. Three
different competitive reactions are potentially in operation; path-
way ‘a’ results in the retro-epoxide opening leading to the Int-3
and epoxide 6a whereas pathways ‘b’ and ‘c’ furnish the spirocyclic
compounds 8a and 9a, respectively.
2-Halopyridine N-oxides are known to undergo SNAr processes
at C-2 at low temperatures.13 Consequently, we envisioned 2-halo-
pyridine N-oxide as a substrate for the regioselective cyclization to
provide 11 following reaction pathway ‘b’. Assuming that the
Smiles rearrangement might be avoided if the reaction was per-
formed at lower temperatures, we attempted the cyclization of
N-Cbz-protected pyridine-N-oxide14 10 at 0 °C. Base-mediated
cyclization of 10 at 0 °C afforded a mixture of regioisomers 11
The optimized epoxide opening reaction conditions were then
applied to the ring-opening of 6a–d with aromatic and heteroaro-
matic alcohols 5b–e to afford the tertiary alcohols 7b–h as the only
products22 (Table 2). These relatively mild conditions (K2CO3/DMF/
100 °C) compared to the literature method (NaH/DMF/100 °C)7 im-
proved significantly the product yield especially for pyrrolidine
epoxides 6c and 6d (entries 5 and 6, Table 2).
O
O-
'path a'
+
c
N
N
Cl
Bn
Int-3
6a
NBn
The structures of products 7b–h were confirmed from 1H NMR
data. The presence of two singlets between d 3.60–3.65 ppm (CH2–
N) and d 3.80–3.90 ppm (CH2–O) confirmed the desired epoxide
opening at the less-hindered carbon of the epoxide.
O
'path b'
'path c'
8a
O-
a
N
Cl
BnN
Int-1
b
The alcohols 7b–h were then subjected to our optimized cycli-
zation conditions. The reaction proved to be general across a num-
ber of substituted pyridines, quinoline and a phenyl.23 Further both
piperidine (six-membered) and pyrrolidine (five-membered)
derivatives underwent smooth cyclization. Similar to 8a, the chem-
ical structures for spirocycles 8b–g were assigned based on the
O-
O
9a
Smiles
rearrangement
Cl
N
Int-2
Scheme 2. Plausible pathways for the competitive reactions occurring during the
formation of products 8a and 9a.

4352
Tony K.A. et al. / Tetrahedron Letters 51 (2010) 4350–4353
Table 2
C–O bond forming reactions in 2-chloropyridines and an aromatic bromide leading to spirocyclic compound 8
R
N
6a-d
OH
O
Pd(OAc)2
K2CO3, DMF
100 oC
( )n
OH
7a-h
O
Y
X = N, C
Y = Cl, Bn
n = 0, 1
( )n
N
BINAP, K 2CO3
toluene, reflux
X
Y
n = 0, 1
X
O
8a-h
5a-e
R
X
Entry
1
Substratea
OH
Epoxide
Intermediate
Yieldb (%)
Productc
Yieldd (%)
80
Bn
O
O
N
N
Bn
N
N
O
8a
N
80
75
7a
N
N
N
O
O
O
Cl
N
N
6a
Cl
HO
5a
Bn
Boc
O
Boc
O
2
3
5a
68
83
8b
7b
N
6b
Cl
N
Boc
HO
O
O
O
Bn
N
OH
8c
6a
80
70
N
N
5b
N
Bn
7c
Bn
Cl
Cl
HO
Ph
Ph
Ph
O
8d
N
OH
O
N
O
4
6a
65
7d
N
N
N
Bn
Cl
Cl
HO
5c
Bn
O
O
O
O
N
N
Bn
N
8e
5
6
5a
5b
65
85
68
76
N
Cl HO
6c
7e
N
Bn
O
Boc
O
N
O
Boc
N
8f
N
O
N
6d
7f
N
Boc
Cl
HO
Bn
O
O
H3C
OH
N
O
H3C
N
7
8
6a
6a
75
78
70
60
N
8g
H3C
N
O
O
Cl
N
7g
5d
Cl
HO
N
Bn
OH
Bn
O
Br
8h
N
7h
Br
HO
5e
Bn
a
b
c
Reactions were carried out with 1–2 mmol if 5.
Isolated yields of intermediate 7a–h.
Reaction were carried out with 0.50–1.0 mmol of 7.
Isolated yield of products 8a–h.
d
chemical shift of the CH2–O group before and after cyclization. For
all spirocycles 8b–g the changes in the chemical shift for CH2–O
group was negligible before and after cyclization indicating exclu-
sive desired spirocycle formation (see Supplementary data). The
analytical data for 8h was in full agreement with the data available
in the literature.10
Supplementary data
Supplementary data (1H NMR and mass spectra) associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.06.061.
In conclusion, a convenient and regioselective synthetic path-
way to 3-substituted-2,3-dihydro-spiro[1,4]dioxino[2,3-b]pyridine
derivatives via efficient epoxide opening and a subsequent palla-
dium-catalyzed cyclization sequence is described. To the best of
our knowledge, this is the first report on the selective synthesis
of spirocycles of type 8a–h in good yields. The methodology
worked well with a variety of substituents on the pyridine rings.
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opening of epoxides: To a solution of 5a–e (1.00 mmol) and epoxide 6a–d
(1.10 mmol) in DMF (2.0 mL) was added K2CO3 (3.00 mmol) and the mixture
was heated at 100 °C for 3–6 h. When the reaction was complete (TLC and LC–
MS analyses) the reaction mixture was diluted with water and extracted with
EtOAc, washed with water and brine, and dried over Na2SO4. The solvent was
evaporated under reduced pressure and purification by silica-gel
chromatography using EtOAc/hexanes eluent systems afforded 7a–h.
23. Representative procedure for the palladium-catalyzed intramolecular C–O bond
formation: A solution of 7a–h (0.50 mmol) in toluene (5.0 mL) was added to a
Schlenck tube and degassed under argon for 15 min. Then Pd(OAc)2
(0.05 mmol), BINAP (0.06 mmol) and, K2CO3 (0.60 mmol) were added and the
mixture was heated at 125 °C for 5–8 h. When the reaction was complete, the
mixture was filtered through
a short pad of Celite. The filtrate was
concentrated in vacuo and purified by silica-gel chromatography to give
compounds 8a–h.
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