New and efficient RCM in pyridinic series: synthesis of 2H-dihydropyrano- or 2,3H-dihydrooxepino[3,2-b]pyridines

Article abstract of DOI:10.1016/j.tetlet.2006.06.139

A new and very efficient route to polycyclic heterocycles with isosteric replacement of benzene by pyridine is reported. This strategy involving the RCM reaction in pyridinic series as a keystep allows us to prepare 2H-dihydropyrano- or 2,3H-dihydrooxepino[3,2-b]pyridines 1 and 2 in very good overall yields (47% and 44%, respectively).

Full text of DOI:10.1016/j.tetlet.2006.06.139

Tetrahedron Letters 47 (2006) 6235–6238
New and efficient RCM in pyridinic series: synthesis
of 2H-dihydropyrano- or 2,3H-dihydrooxepino[3,2-b]pyridines
Estelle Banaszak, Corinne Comoy and Yves Fort*
`
Synthese Organometallique et Reactivite, UMR CNRS-UHP 7565, Faculte des Sciences et Techniques,
Universite´ Henri Poincare´ Nancy 1, BP 239, Bd des Aiguillettes, 54506 Vandoeuvre-les-Nancy, France
´
´
´
´
Received 19 May 2006; revised 23 June 2006; accepted 27 June 2006
Abstract—A new and very efficient route to polycyclic heterocycles with isosteric replacement of benzene by pyridine is reported.
This strategy involving the RCM reaction in pyridinic series as a keystep allows us to prepare 2H-dihydropyrano- or 2,3H-
dihydrooxepino[3,2-b]pyridines 1 and 2 in very good overall yields (47% and 44%, respectively).
ꢀ 2006 Elsevier Ltd. All rights reserved.
O
Challenge posed by the development of a new series of
derivatives, which present a potential biological activity,
a great interest is displayed for the syntheses of polyhet-
erocycles. In this context, we focus our attention to elab-
orate short and efficient access to polyheterocyclic
pharmacophores with isosteric replacement of benzene
by pyridine. For such a substitution of benzene by pyr-
idine, one needs to develop novel synthetic strategies. As
an example, we recently reported an original prepara-
tion of thieno[3,2-b]pyridines.1 In our ongoing research,
we gave our attention to pyrano- or oxepinopyridines.
The outstanding interest of these frameworks is to allow
further numerous functionalizations on nonaromatic
rings (e.g., hydroxyamination, dihydroxylation, epoxi-
dation) or/and on pyridinic moiety (e.g., metallation/
halogenation, cross coupling, arylamination).
O
N
N
2
1
Figure 1. Structure of 1 and 2.
developed a similar Claisen rearrangement of substi-
tuted propargylic ether as a route to 2,2-dimethyl ana-
logues of 1. On the other hand, numerous syntheses of
substituted 2- or 4-azacoumarins are documented in
the literature5 and Briger and co-workers6 recently pat-
ented the preparation of 4-azacoumarine, the carbonyl
analogue of 1.
Since the last decade, the ring-closing metathesis (RCM)
strategy has been largely explored for carbocyclic- or
heterocyclic ring construction with some direct applica-
tions to natural product syntheses.7 Amongst the vari-
ous examples described in the literature, very few are
carried out using pyridine units.8
To our knowledge, whereas no reference reports the
preparation of 2,3H-dihydrooxepino[3,2-b]pyridine
2 as benzoxepine isoster, only a few papers described
the preparation of 2H-dihydropyrano[3,2-b]pyridine 1,
isostere of chromens (Fig. 1). Indeed only Sliwa and
co-workers2 proposed various multi-step accesses to
heterocycle 1 but in very moderate overall yields (11–
15%) and Schmidt and co-workers3 obtained 1 after a
thermolysis Claisen rearrangement of propynylpyridinyl
ether but only in a mixture with furopyridines as
side products. It is noteworthy that Evans and Stemp4
Herein we reported the first synthetic approach to het-
erocycles 1 and 2 involving an RCM reaction of O-alken-
ylpyridines. The key RCM sequence has been performed
using ruthenium complexes A or B (Fig. 2).
The retrosynthetic analysis of compounds 1 and 2 is out-
lined in Scheme 1. The targeted molecules 1 and 2 could
be disconnected to 3-alkenyloxy-2-vinylpyridines, which
could be obtained starting from the commercially avail-
able 2-bromo-3-hydroxypyridine.
Keywords: 2H-dihydropyrano[3,2-b]pyridine; 2,3H-dihydrooxepino-
[3,2-b]pyridine; Stille cross coupling; RCM reaction.
*
Corresponding author. E-mail: yves.fort@sor.uhp-nancy.fr
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.139

6236
E. Banaszak et al. / Tetrahedron Letters 47 (2006) 6235–6238
O
O
RCM
n
N
N
Mes
Mes
Ph
n
PCy
3
Grubb's catalyst A or B
toluene, 70 °C
Cl
N
n=1
n=2
N
n=0
n=1
Cl
Ru
Ru
Ph
7
8
1
2
73%
71%
Cl
Cl
PCy
PCy
3
3
st
nd
1
generation
2
generation
Scheme 3. RCM reaction of 7–8 to 1–2.
Grubb's catalyst, A
Grubb's catalyst, B
Figure 2.
afford 2H-dihydropyrano[3,2-b]pyridine 1 and 2,3H-
dihydrooxepino [3,2-b]pyridine 2 (Scheme 3).
O
O
To optimize the ring construction, we planed to com-
pare the two generations of Grubb’s catalyst A (first
generation) and B (second generation) (Table 1). The
ring closure reaction was performed using 7 or 8
(1.0 mmol) and Grubb’s catalyst (A or B) (4–
10 mol %) in toluene at 70 ꢁC. Employing A for the
RCM reaction on 3-allyloxy-2-vinylpyridine 7 yielded
23% after stirring for 5 h at 70 ꢁC, and an increase in
yield of 1 to 68% was noted when the reaction time
was extended to 24 h (Table 1, entries 1–3). Using the
later version of Grubb’s catalyst B led to an efficient
RCM to afford the targeted compound with good to
excellent yields (Table 1, entries 4–6). The best result
was obtained using 10 mol % of the second generation
of Grubb’s catalyst B, in toluene at 70 ꢁC for 24 h.12
n
n
N
N
n=1, 2
n=0 1 or n=1 2
OH
N
Br
Scheme 1. Retrosynthetic route to 1 and 2.
3-Hydroxy-2-vinylpyridine 6 was prepared by a Stille
cross coupling using the acetate of 2-bromo-3-hydroxy-
pyridine 3 and vinyltributyltin (1.1 equiv), bis(triphen-
ylphosphine)palladium(II)dichloride (Pd(PPh3)2Cl2, 5
mol %) as catalyst and in refluxing DMF as solvent
(Scheme 2).9 Deprotection of the crude vinyl product 4
was then performed using K2CO3 (1 equiv) in MeOH
at rt for 1 h to afford the expected derivative 610 in an
excellent yield (81% starting from 2-bromo-3-hydroxy-
pyridine). O-allylation or O-butenylation of 3-hydroxy
derivative 6 was finally carried out using sodium hydride
(1.2 equiv or 2 equiv, respectively) and allylbromide
(1.2 equiv) or 4-bromo-1-butene (2 equiv) in DMF to
yield 3-allyloxy-2-vinylpyridine 7 and 3-butenyloxy-2-
vinylpyridine 8 in 79% and 77%, respectively.11
In spite of the longer reaction time or increase of cata-
lyst quantity, total conversion of 7 was not observed
and the substrate was recovered in mixture with pyrano-
pyridine 1. Moreover, no degradation of the reaction
solution was deplored. On the other hand, when the
RCM reaction was performed with a reaction time up
to 24 h no modification was observed (no variation in
yield or degradation). Increase in the yield of 1 was clo-
sely bound to the catalyst quantity. It can be assumed
that the pyridine moiety might block a coordination site
of ruthenium catalyst and, consequently, inhibit the
RCM (entries 4–6).
As mentioned above, the key step of our synthetic route
to 1 and 2 was the ring closing metathesis (RCM) to
Applied to 8, this methodology allowed the synthesis of
2,3H-dihydrooxepino[3,2-b]pyridine 2 in a 71% isolated
yield (Scheme 3).13
OAc
Br
OH
Br
Stille Cross Coupling
AcCl, Et3N
see ref. 9
It is interesting to note that we firstly envisioned the syn-
thesis of dihydrooxepino[3,2-b]pyridine by RCM using
3-allyloxy-2-allylpyridine 9 (Scheme 4). Allylic deriva-
tive 9 was prepared according to the procedure
described for 7 and 8, using allyltributyltin for Stille
PdCl2(PPh3)2 (5 mol%)
Bu3Sn-CH=CH2
DMF, 24 h,110 °C
N
N
3
OH
OAc
K2CO3, MeOH
1 h, rt
Table 1. RCM on 3-allyloxy-2-vinylpyridine 7
N
N
Entry
Catalyst
(mol %)
Reaction
time (h)
Yieldsa of 1 (%)
4
6
81%
1
2
3
4
5
6
A
A
A
B
B
B
4
6
10
4
6
10
5
24
24
5
24
24
23
60
68
44
65
73
NaH, 1 h, 0°C then,
Br-(CH2)n-CH=CH2
O
n
n=1 7 79%
n=2 8 77%
N
DMF, 3 h,rt
or 24 h,40 °C
a After chromatography on silica gel.
Scheme 2. Synthesis of 3-alkenyloxy-2-vinylpyridines 7–8.

E. Banaszak et al. / Tetrahedron Letters 47 (2006) 6235–6238
6237
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1–2, 75–82; (d) Bohn, B.; Heinrich, N.; Vorbrueggen, H.
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O
O
RCM
N
N
N
9
10
Isomerization
silica gel
O
RCM
1
88%
Grubb's catalyst B
toluene, 70 °C, 4 h
6. Bridger, G.; Skerlj, R.; Kaller, A.; Hartwig, C.; Bogucki,
D.; Wilson, T. R.; Crawford, J.; McEachern, E. J.; Astma,
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11
Scheme 4. Isomerization-RCM tandem.
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4450; (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D.
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cross coupling, in 43% yield starting from 2-bromo-3-
hydroxypyridine. Treatment of 9 under various RCM
conditions (temperature, catalyst loading) did not afford
the expected heterocycle 10, in these experiments only
isomerization of 9 to 11 was observed in moderate yield.
Taking into account this result, we performed the total
isomerization of 9 to 11 by a successful treatment on sil-
ica gel. After which, we realized the RCM of 11 (catalyst
B, 10 mol%) to yield 1 in 88%, after 4 h at 70 ꢁC in tol-
uene. Despite this excellent result for RCM, this syn-
thetic sequence via 9 seemed less efficient than the
procedure described in Scheme 3 because it afforded
pyranopyridine 1 only in 38% overall yield starting from
2-bromo-3-hydroxypyridine.
446–452; (d) Furstner, A.; Guth, O.; Rumbo, A.; Seidel,
¨
G. J. Am. Chem. Soc. 1999, 121, 11108–11113; (e)
Stefinovic, M.; Snieckus, V. J. Org. Chem. 1998, 63,
2808–2809; (f) Deiters, A.; Martin, S. F. Chem. Rev. 2004,
104, 2199–2238; (g) Van Otterlo, W. A. L.; Ngidi, E. L.;
Kuzvidza, S.; Morgans, G. L.; Moleele, S. S.; De Koning,
C. B. Tetrahedron 2005, 61, 9996–10006; (h) Van Otterlo,
W. A. L.; Ngidi, E. L.; De Koning, C. B. Tetrahedron Lett.
2003, 44, 6483–6486; (i) Hong Nguyen, V. T.; Bellur, E.;
Langer, P. Tetrahedron Lett. 2006, 47, 113–116; (j)
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96; (k) Chang, S.; Grubbs, R. H. J. Org. Chem. 1998, 63,
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Villieras, J.; Lebreton, J. J. Org. Chem. 2001, 66, 6305–
In summary, we have succeeded in preparing expected
2H-dihydropyrano[3,2-b]pyridine 1 and 2,3H-dihydro-
oxepino[3,2-b]pyridine 2 in good yields starting from
commercial 2-bromo-3-pyridinol (47% and 44%, respec-
tively) and we have developed new, versatile and effi-
cient syntheses using an RCM reaction with pyridine
units as substrates. The extension of this work to the
preparation of other potential biological scaffolds
including fused heterocyclic moieties is currently under
investigation.
6312; (b) Van Otterlo, W. A. L.; Morgans, G. L.; Khanye,
S. D.; Aderibigbe, B. A. A.; Michael, J. P.; Billing, D. G.
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41, 8053–8057.
10. An other way to prepare 6 is described by Knochel: Kopp,
F.; Krasovskiy, A.; Knochel, P. Chem. Commun. 2004,
2288–2289.
11. Preparation of 3-allyloxy-2-vinylpyridine 7.
3-Hydroxy-2-vinylpyridine 69,10 (1.763 g, 14.6 mmol) in
solution in distilled DMF (20 mL) was added to sodium
hydride (0.461 g, 19.2 mmol), at 0 ꢁC, under a nitrogen
atmosphere. After stirring at 0 ꢁC for 1 h, a solution of
allyl bromide (1.7 mL, 19.2 mmol) in DMF (10 mL) was
added dropwise. Then the reaction medium was allowed to
stir at room temperature for 3 h. The resulting solution
was rapidly washed with a saturated aqueous NH4Cl
solution and extracted with dichloromethane (2 · 10 mL).
After drying (MgSO4), filtration and solvent evaporation,
the crude product was purified by column chromato-
graphy on a silica gel (0.063–0.200 mm, eluent: hexane/
AcOEt 70:30), which yielded 3-allyloxy-2-vinylpyridine
7 (1.736 g, 79%) as an orange wax. 1H NMR: dH 4.56 (dd,
J = 3.6, 1.4 Hz, 2H), 5.30 (dd, J = 10.5, 1.3 Hz, 1H), 5.42
(dd, J = 17.2, 2.1 Hz, 1H), 5.47 (dd, J = 10.9, 2.1 Hz, 1H),
6.05 (m, 1H), 6.38 (dd, J = 17.4, 2.1, 1H), 7.15 (m, 3H),
8.18 (dd, J = 4.10, 1.52, 1H); 13C NMR: dC 69.16, 118.07,
118.74, 119.46, 123.16, 130.84, 132.68, 141.40, 145.54,
152.05; MS (EI) m/z 162 ([M+H]+, 8), 161 (M+, 52), 160
([MÀH]+, 63), 146 (45), 120 (100), 92 (86), 79 (28), 65 (60);
IR (NaCl) m 3020, 1578, 1442, 784.
Acknowledgements
We gratefully acknowledge the financial support from
CNRS and UHP. We thank Sandrine Adach for record-
ing low resolution mass spectra.
References and notes
1. Comoy, C.; Banaszak, E.; Fort, Y. Tetrahedron 2006, 62,
6036–6041.
2. (a) Sliwa, H.; Krings, K. P. Heterocycles 1979, 12, 493–
495; (b) Billeret, D.; Blondeau, D.; Sliwa, H. Tetrahedron
Lett. 1991, 32, 627–628; (c) Billeret, D.; Blondeau, D.;
Sliwa, H. Synthesis 1993, 881–884.
3. Bruhn, J.; Zsindely, J.; Schmidt, H. Helv. Chim. Acta
1978, 61, 2542–2559.
4. Evans, J. M.; Stemp, G. Synth. Commun. 1988, 18, 1111–
1118.
12. Preparation of 2H-dihydropyrano[3,2-b]pyridine 1.
Grubb’s second generation catalyst (10 mol %) was added
to a degassed solution of 3-allyloxy-2-vinylpyridine 7
5. For examples, see: (a) Moffet, R. B. J. Org. Chem. 1970,
35, 3596–3600; (b) Von Strandtmann, M.; Connor, D.;

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E. Banaszak et al. / Tetrahedron Letters 47 (2006) 6235–6238
(0.161 g, 1 mmol) dissolved in degassed and anhydrous
method described for 1, using second generation Grubb’s
catalyst (10 mol %) for 16 h at 70 ꢁC and yielded 2 in 71%
yield (77 mg) as a brown oil. 1H NMR: dH 2.74 (m,
2H), 4.26 (m, 2H), 6.25 (m, 2H), 6.72 (d, J = 12.1 Hz, 1H),
7.08 (dd, J = 9.2, 4.5 Hz, 1H), 7.27 (d, J = 9.2 Hz, 1H),
8.30 (d, J = 4.5 Hz, 1H); 13C NMR: dC 34.12, 69.69,
122.07, 127.16, 130.87, 133.47, 143.15, 145.94, 155.50; MS
(EI) m/z 148 ([M+H]+, 8), 147 (M+, 85), 146 ([MÀH]+,
100), 132 (38), 118 (21), 91 (15), 78 (9), 65 (15); IR
(NaCl) m. 3053, 2913, 1651, 1436, 1221, 994, 790. HRMS
(ES+) calcd for C9H9NO = 147.0685, found [M+H+]:
148.0776.
toluene (20 mL). The reaction mixture was then heated at
70 ꢁC for 24 h under a nitrogen atmosphere. After removal
of the solvent under reduced pressure, the residue was
purified by column chromatography on a silica gel (0.063–
0.200 mm, eluent: hexane/AcOEt 70:30) which yielded 2H-
pyrano[3,2-b]pyridine 1 (97 mg, 73%) as an orange oil. The
spectroscopic data are in conformity with literature data
(Ref. 2).
13. Preparation of 2,3H-dihydrooxepino[3,2-b]pyridine 2.
The RCM reaction of 3-butenyloxy-2-vinylpyridine 8
(130 mg, 0.74 mmol) was performed according to the