Synthesis of substituted pyrano[3,2-c]pyridines via Diels-Alder reaction of 3-methylenepyridin-4-one

Article abstract of DOI:10.1016/j.tetlet.2005.10.119

On heating, the di-Boc-pyridin-4-one derivative 7 gave an unstable 3-methylenepyridin-4-one intermediate 3, which underwent a rearomatising Diels-Alder cycloaddition with activated alkenes to give substituted pyrano[3,2-c]pyridines in moderate yields.

Full text of DOI:10.1016/j.tetlet.2005.10.119

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 39–41
Synthesis of substituted pyrano[3,2-c]pyridines via
Diels–Alder reaction of 3-methylenepyridin-4-one
Kirill Tchabanenko, Marcus G. O. Taylor, Robert M. Adlington and Jack E. Baldwin*
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK
Received 6 September 2005; revised 19 October 2005; accepted 25 October 2005
Available online 14 November 2005
Abstract—On heating, the di-Boc-pyridin-4-one derivative 7 gave an unstable 3-methylenepyridin-4-one intermediate 3, which
underwent a rearomatising Diels–Alder cycloaddition with activated alkenes to give substituted pyrano[3,2-c]pyridines in moderate
yields.
Ó 2005 Elsevier Ltd. All rights reserved.
Pyrano[3,2-c]pyridine 1 derivatives are known to possess
various important biological properties such as anti-
allergic, anti-inflammatory and estrogenic activities.1
Several biologically active naturally occurring alkaloids
of plant origin contain a pyranopyridine moiety. Most
recently pyranoquinolines like 2 were shown to inhibit
R'
R'
R''
OH
O
O
∆
R''
X
2
N
N
N
4
3
1
Eg5 proteins and their application in cancer treatment
3
X = OAc
or halide
is currently under investigation.
R N
2
It was our expectation that pyrano[3,2-c]pyridine deriv-
atives 1 can be synthesised via a reverse electron demand
rearomatising Diels–Alder reaction of 3-methylenepyri-
din-4-one 3 with alkenes (Scheme 1). Previously, we
demonstrated application of such cycloaddition reac-
tions of tropolone-methides and ortho-quinone-meth-
O
F3C
N
H
Ar
2
4
ides in biomimetic syntheses of natural products. We
Scheme 1. Diels–Alder approach to pyranopyridines 1.
anticipated, based on our previous findings, that the
reactive intermediate 3 will be accessed on thermal treat-
ment of a 4-hydroxy-pyridine derivative 4, possessing a
good leaving group substituent X on the methylene at
C3.
ation was addressed based upon a previously reported
method for demethylation of 4-methoxypyridine. We
7
found that in our case demethylation occurred at a
7
milder temperature of 100 °C (lit., 180 °C).
Our synthesis of the cyclisation precursor started with
commercially available 4-methoxypyridine (Scheme 2).
Formylation of the 3-position was achieved following
Isolation of the highly polar 6 was problematic and we
decided instead upon an in situ protection. Addition
of excess Boc-anhydride and triethylamine to the crude
reaction mixture resulted in formation of the di-Boc-
pyridin-4-one 7, which was obtained as a pale yellow
oil after column chromatography.
5
a literature method, which we modified to obtain a
6
higher yield of the crude aldehyde 5, which was used
in the following step without column chromatography.
Reduction of the aldehyde was carried out according
4
d
to our previously established method. Next demethyl-
Next, we attempted a direct reaction of 7 with dihydro-
pyran, hoping that the nitrogen deprotection would oc-
cur under heating. To our delight, the reaction yielded
*
Corresponding author. Tel.: +44 (0) 1865 275 671; fax: +44 (0) 1865
75 670; e-mail: jack.baldwin@chem.ox.ac.uk
2
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.119

40
K. Tchabanenko et al. / Tetrahedron Letters 47 (2006) 39–41
Table 1. Results of reactions of 7 with alkenes
OMe
N
OMe O
OMe
Alkene
Product
Yield (%)
50
,tBuLi
BH3 DMS
Br
H
OH
O
O
5
2%
then DMF
1
N
N
for 2 steps
N
8
O
H
5
O
Boc O,
Et N
3
O
Me
2
(
TMS) S,
O
O
O
O
2
O
NaOMe
OBoc
OH
2
3
4
5
55
65
55
70
O
N
N
N
N
O
45 %
N
H
N
H
for two steps Boc
N
N
OMe
OMe
7
6
9
1
H
H
O
O
O
OMe
OMe
OMe
o
N
1
30 C,
H
sealed
tube
0
8
: 50%
H
OMe
Scheme 2. Synthesis of the cycloaddition precursor 7.
a
1
1
Me
the desired cycloadduct 8 as a single stereoisomer. The
relative stereochemistry at the ring junction was estab-
lished by NOE analysis.
Me
OMe
MeO
O
6
7
8
52
51
79
1
2
N
We performed the reaction of 7 with a number of acti-
vated cyclic and non-cyclic alkenes and the results of
our investigation are presented in Table 1. Whereas
dihydropyran (entry 1) and 2-methyldihydrofuran (en-
try 2) are commercially available, cyclic methoxyalkenes
H
OMe
OMe
O
b
13
14
N
N
9
and 10 were prepared in a single step procedure from
OH
8
the corresponding ketones. Preparation of methoxyalk-
enes 12–15 required synthesis of the dimethoxy ketals
9
followed by a mild conversion into the methoxyalkenes
O
O
1
0
employing an excess of tri-isobutyl aluminium. All
reactions with such cyclic activated alkenes gave
Diels–Alder products in moderate yields as single stereo-
isomers. Interestingly, when we attempted to prepare the
methoxyalkene 12 according to the single-step proce-
OH
Ph
OMe
9
1
N
77
—
Ph 15
8
dure, we ended up with a 4:1 mixture of 12 and the iso-
0
No reaction
meric form 11. We expected the Diels–Alder reaction to
prefer the less hindered double bond of 12; surprisingly,
3
showed a high preference for the tetrasubstituted dou-
All reactions were carried out according to the example synthesis of
12
ble bond of 11. A single stereoisomer was also formed in
the reaction with pure 12, this time prepared via a two-
step procedure, showing a high level of stereocontrol
by the centre adjacent to the alkene. Reaction of the
trisubstituted alkene 13 resulted in further elimination
9
,
but (a) the reaction was carried out using a 4:1 mixture of enolates
12 and 11; (b) 13 consisted of a 1:1 mixture of E and Z enolates.
1
0
O
(
entry 7), while terminal enol ethers 14 and 15 gave
O
t
1
1
O
O Bu
o
quinone-methide Michael addition products.
130 C
N
O
N
All reactions proceeded with full consumption of the
starting material and a white highly polar solid was
recovered in every case accounting for the consumed
starting material. It is presumed that it consisted of
products of oligomerisation, which were not character-
ised on this occasion. Finally, the reaction with methyl
cyclohexene (entry 10) gave no isolated cycloaddition
product but instead evidence of oligomerisation.
O
O
7
3
Scheme 3. Proposed mechanism for formation of 3.
In conclusion, we have demonstrated the first examples
of a Diels–Alder reaction of 3-methylenepyridin-4-one
with activated alkenes. The reaction proceeded with for-
mation of substituted pyrano[3,2-c]pyridines in moder-
ate yields with high levels of stereocontrol. Further
Our proposed mechanism for in situ formation of 3-
methylenepyridine-4-one 3 is presented in Scheme 3.

K. Tchabanenko et al. / Tetrahedron Letters 47 (2006) 39–41
41
investigations will centre on reactions in polar solvents
with a wider range of alkenes. The influence of Lewis
acids and the possibility of an intramolecular Diels–
Alder reaction of a derivative of 7 possessing a tethered
alkene moiety will also be investigated.
2002, 4, 3009; (d) Rodriguez, R.; Adlington, R. M.;
Moses, J. E.; Cowley, A.; Baldwin, J. E. Org. Lett. 2004, 6,
3
617.
. Comins, D. L.; Killpack, M. O. J. Org. Chem. 1990, 55,
9.
5
6
6
. We used a larger amount of DMF (5 equiv) to quench the
lithiated pyridine and allowed the reaction to warm up to
0
°C before the final addition of water. Ethyl acetate was
Acknowledgements
used instead of diethyl ether for extraction. The crude
product was obtained in 85% yield.
We would like to thank the CRL NMR staff, especially
Dr. Barbara OÕDell, for their help with structure
elucidation.
7
. Shiao, M. J.; Ku, W. S.; Hwu, J. R. Heterocycles 1993, 36,
3
23.
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10. Cabrera, G.; Fiaschi, R.; Napolitano, E. Tetrahedron Lett.
001, 42, 5867. We discovered that potassium sodium
9
1
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4
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1
1
14
2
+
À1
(M+H ) requires 192.1025; mmax/cm (film) 2939, 1580,
1490, 1273, 1165, 1100, 936, 909, 830; dH (500 MHz,
2
005, 289 pp.
CDCl ) 1.60 (1H, m), 1.68–1.77 (3H, m), 2.25 (1H, m),
2.68 (1H, dd, J 16.5, 4.5), 2.94 (1H, dd, J 16.5, 6.0), 3.77
(1H, m), 4.00 (1H, m), 5.42 (1H, d, J 2.5), 6.80 (1H, d, J
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23.5, 24.0, 26.1, 31.3, 62.5, 97.1, 111.6, 116.3, 149.0, 150.7,
159.7.