General synthetic approach to 4-substituted 2,3-dihydrofuro[2,3-b]pyridines and 5-substituted 3,4-dihydro-2H-pyrano[2,3-b]pyridines

Article abstract of DOI:10.1055/s-0028-1087485

An efficient strategy for the synthesis of functionalised 2,3-dihydrofuro[2,3-b]pyridines and 3,4-dihydro-2H-pyrano[2,3-b]pyridines is reported. The strategy is based on an intramolecular inverse-electron-demand Diels-Alder reaction starting from 1,2,4-tr

Full text of DOI:10.1055/s-0028-1087485

92
LETTER
General Synthetic Approach to 4-Substituted 2,3-Dihydrofuro[2,3-b]pyridines
and 5-Substituted 3,4-Dihydro-2H-pyrano[2,3-b]pyridines
Dihydrofuro- and
o
ihydropyr
a
u
b
]pyr
s
idine
s
sef Hajbi,a,b Franck Suzenet,*a Mostafa Khouili,b Said Lazar,c Gérald Guillaumet*a
a
Institut de Chimie Organique et Analytique (ICOA), UMR-CNRS 6005, University of Orléans, B. P. 6759, 45067 Orléans, France
E-mail: gerald.guillaumet@univ-orleans.fr; E-mail: franck.suzenet@univ-orleans.fr
b
c
Laboratoire de Chimie Organique et Analytique, Université Sultan Moulay Slimane FST, BP 523, 23000 Beni-Mellal, Morocco
Laboratoire de Biochimie, Environnement et Agroalimentaire, University Hassan II-Mohammedia FST, BP 146, 20800 Mohamedia,
Morocco
Fax +33(2)38417281
Received 21 July 2008
N
N
N
N
Abstract: An efficient strategy for the synthesis of functionalised
2,3-dihydrofuro[2,3-b]pyridines and 3,4-dihydro-2H-pyrano[2,3-
b]pyridines is reported. The strategy is based on an intramolecular
inverse–electron-demand Diels–Alder reaction starting from 1,2,4-
triazines appropriately functionalised with alkynes, followed by
various cross-coupling reactions (Suzuki, Stille, and Sonogashira).
N
MCPBA, CH2Cl2
r.t., 4 h
N
R
SMe
R
SO2Me
1 R = H (61%)
2 R = Ph (87%)
Scheme 1 Synthesis of the starting 3-methylsulfanyl-1,2,4-triazines
1 and 2
Key words: inverse-electron-demand Diels–Alder reactions, dihy-
drofuro[2,3-b]pyridines, dihydropyrano[2,3-b]pyridines, cycload-
dition, microwave activation
N
N
N
N
HO
N
N
NaH, THF
r.t., 1 h
R
O
R
SO2Me
The inverse-electron-demand Diels–Alder cycloaddition
between electron-deficient heteroaromatic azadienes and
electron-rich dienophiles is a fundamental reaction for the
construction of a wide variety of fused heterocyclic sys-
tems.1 Among electron-deficient heteroaromatic aza-
dienes, our group and others have been particularly
interested in the use of 1,2,4-triazines because of their
propensity to undergo [4+2] cycloaddition reactions
across the C3/C6 diene (with subsequent elimination of
molecular nitrogen) with alkynes.2
1 R = H
3 R = H
(59%)
2 R = Ph
4 R = Ph (74%)
Br
NBS, AgNO3
N
N
acetone
r.t., 2 h
N
R
O
5 R = H (52%)
6 R = Ph (48%)
Scheme 2 Synthesis of bromoalkynes 5 and 6
We recently reported that intramolecular Diels–Alder
reaction of 1,2,4-triazines tethered to an alkyne by an
ether linker allowed easy access to substituted 2,3-dihy-
drofuro[2,3-b]pyridines and 3,4-dihydro-2H-pyrano[2,3-
b]pyridines2a that are of interest for their structural simi-
larities to known biologically active quinolines, substitut-
ed pyridines, and chromanes.3 Our initial strategy
involved the introduction of a substituent at the terminal
position of the alkyne via Sonogashira coupling prior to
the Diels–Alder cycloaddition. Nevertheless, this route
showed some limitations; for example, only coupling re-
actions occurring on alkynes were tolerated before the
cyclisation step. We sought for an alternative methodolo-
gy that would not only extend the substitution pattern on
the products but also allow functionalisation to be carried
after the cycloaddition step.
philes. Depending on the substituent on the starting tri-
azine, the leaving group can either be a sulfone or a
halogen, the first one being more useful due to its ready
availability. Thus, 3-methylsulfanyl-1,2,4-triazines 1 and
2 were synthesized by oxidation of the corresponding
thioethers with MCPBA (Scheme 1).2m The difficulties in
isolating water-sensitive compound 1 were in part solved
by precipitation of the triazine from the crude reaction
mixture employing a petroleum ether–ethyl acetate
(60:40) mixture.
Nucleophilic displacement of methylsulfinate from 1 and
2 by the sodium salt of homopropargylic alcohol afforded
3-(4-pentynyloxy)-1,2,4-triazines 3 and 4 following re-
ported procedures.2m The bromine was then introduced se-
lectively at the terminal position of the alkynes following
the procedure of Li and Wu,4 allowing the formation of
the corresponding bromoalkynes 5 and 6 in 52% and 48%
yield, respectively (Scheme 2).
Our strategy involves the initial functionalisation of the
1,2,4-triazine ring at C-3 with different alkoxy nucleo-
Using this strategy to prepare 3-(3-butynyloxy)-1,2,4-tri-
azines 8 and 9 gave only low yields of the expected prod-
SYNLETT 2009, No. 1, pp 0092–0096
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1087485; Art ID: D28008ST
x
x.
x
x.
2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

LETTER
Dihydrofuro- and Dihydropyrano[2,3-b]pyridines
93
Br
Table 1 Intramolecular Inverse-Electron-Demand Diels–Alder
Reactions under Microwave Irradiation
NBS, AgNO3
HO
HO
acetone
r.t., 2 h
Br
7
(80%)
N
Br
N
chlorobenzene
MW, temp
( )n
(i) NaH, THF
O
R
N
( )n
R
N
O
(ii)
N
N
10–13
5, 6, 8, 9
N
N
Br
R
N
SO2Me
Entry
R
Product
Temp (°C) Time (h)
Yield (%)a
R
N
O
r.t., 1 h
1
2
3
4
H
10, n = 1
11, n = 2
12, n = 1
13, n = 2
180
200
180
200
0.75
82
68
75
71
8 R = H (62%)
9 R = Ph (60%)
H
4
1
2
Scheme 3 Synthesis of bromoalkynes 8 and 9
Ph
Ph
ucts. Hence, the method was adapted and the bromine
introduced prior to the addition to the triazines; 4-bromo-
but-3-yn-1-ol (7) was obtained in 80% yield by treating
commercially available propargylic alcohol with NBS.
Subsequent deprotonation of 7 with NaH followed by the
addition of 1,2,4-triazines 1 and 2 in THF produced 8 and
9 in 62% and 60% yield, respectively (Scheme 3).
a Yield of pure isolated product.
Table 2 Palladium-Catalysed Suzuki Cross-Coupling of Fused
Pyridines 10–13 with 2-Furylboronic Acid
O
Br
Having the tethered triazines 5, 6 and 8, 9 in hand, we in-
vestigated the cycloaddition reaction. We have already re-
ported the inverse-electron-demand Diels–Alder reaction
with arylalkenyl triazines to be very efficient under micro-
wave heating.2a As it allows easy access to high tempera-
tures very rapidly, higher yields were achieved in short
reaction times. Employing the reaction conditions already
developed in our laboratory (chlorobenzene as solvent,
180 °C for five–membered-ring formation and 200 °C for
six-membered-ring formation),5 the corresponding furo-
and pyranopyridines were obtained in high yields. Results
are collected in Table 1.
O
Pd(PPh3)4
( )n
+
( )n
Na2CO3
DME–H2O
OH
B
O
R
N
O
R
N
HO
14–17
10–13
Entry
R
Product
Time (h)
Yield (%)a
1
2
3
4
H
H
14, n = 1
15, n = 2
16, n = 1
17, n = 2
2
74
71
64
75
6
Ph
Ph
12
48
As anticipated, no dehalogenation occurred under the con-
ditions required for the cyclisation. Notably, the introduc-
tion of a halogen at the para position of the pyridine ring
provides a remarkable advantage by allowing further vari-
ations on these bicyclic products. Indeed, bromopyridines
have been widely used for the synthesis of more complex
structures employing metal-catalysed cross-coupling, and
our aim was to determine whether these methodologies
would be applicable with these substrates.
a Yield of pure isolated product.
Table 3 Palladium-Catalysed Stille Cross-Coupling of Fused
Pyridines 13–16 with Allyltributyltin
Br
Pd(PPh3)4
( )n
+
Bu3Sn
( )n
LiCl, DMF
90 °C
O
R
N
First, the Suzuki cross-coupling reaction with fused py-
ridines 10–13 was examined. 2-Furylboronic acid was
chosen as test substrate under standard conditions
[Pd(PPh3)4, Na2CO3 in a DME–H2O (2:1) solvent mix-
ture] and products 14–17 were isolated (Table 2).6
O
R
N
10–13
18–21
Entry
R
Product
Time (h)
Yield (%)a
1
2
3
4
H
18, n = 1
19, n = 2
20, n = 1
21, n = 2
2
2
3
3
62
67
98
79
The ready coupling of 10–13 with arylboronic acids en-
couraged us to examine the Stille cross-coupling of
bromofuro- and bromopyranopyridines 10–13 with allyl-
tributyltin.7 The coupled products 18–21 were isolated
(Table 3).
H
Ph
Ph
a Yield of pure isolated product.
Next, the Sonogashira coupling between aryl bromides
12, 13 and terminal alkynes (trimethysilylacetylene,
phenylacetylene) was studied. Thus, treating compounds
Synlett 2009, No. 1, 92–96 © Thieme Stuttgart · New York

94
Y. Hajbi et al.
LETTER
(i) n-BuLi (2 equiv)
THF, –78 °C
Table 4 Palladium-Catalysed Sonogashira Cross-Coupling of
Fused Pyridines 12 and 13 with Terminal Alkynes
HO
HO
( )n
( )n
SnBu3
(ii) Bu3SnCl (2.2 equiv)
r.t., 3 h
R
26 n = 1 (66%)
27 n = 2 (82%)
Br
Pd(PPh3)2Cl2
(i) NaH, THF
( )n
R
+
N
( )n
(ii)
N
O
CuI, Et3N, DME
60 °C, 24 h
Ph
N
O
Ph
N
Ph
N
SO2Me
SnBu3
22–25
12, 13
2
SnBu3
r.t., 4 h
Entry
R
Product
Yield (%)a
RSMb (%)
N
N
chlorobenzene
N
( )n
1
2
3
4
C6H5
C6H5
TMS
TMS
22, n = 1
23, n = 2
24, n = 1
25, n = 2
52
48
46
44
30
19
30
38
MW
O
Ph
N
( )n
n = 1, 180 °C, 1 h Ph
n = 2, 200 °C, 6 h
O
28 n = 1 (78%)
29 n = 2 (68%)
30 n = 1 (50%)
31 n = 2 (40%)
Scheme 4 Synthesis of stannyl derivatives 30 and 31
a Yield of pure isolated product.
b RSM = recovered starting material.
N
SnBu3
Br
Pd(PPh3)4
12 and 13 in nonoptimised experimental conditions, that
is, DME with Pd(PPh3)2Cl2 (5 mol%), CuI, Et3N, and ter-
minal alkynes, gave cross-coupling products 22–25.8 The
results are summarized in Table 4. This synthetic se-
quence was, however, less efficient than the Suzuki and
the Stille couplings, 22–25 being only obtained in 19–
38% yield along with remaining starting material. No deg-
radation occurred during the reaction and the starting fu-
ro- and pyranopyridines could be recovered.
( )n
+
( )n
O
LiCl, DMF
4 h, 90 °C
O
N
Ph
N
Ph
N
32 n = 1 (71%)
33 n = 2 (68%)
30, 31
Scheme 5 Stille cross-coupling reaction from stannane derivatives
32, 33, and 3-bromopyridine
the synthesis of fused pyridine heterocycles. Reactive
atoms, such as bromine or tin, are compatible with the
synthetic sequence and can in turn be easily replaced by
various functional groups. This novel approach allows a
higher diversity of substituents on the para position of the
pyridine ring via various cross-coupling reactions. The
extension of this work to the preparation of other scaffolds
with potential biological properties including fused het-
erocyclic moieties is currently under investigation.
Although halopyridines are extremely useful intermedi-
ates, other potentially reactive groups on the 4-position
were envisaged. We anticipated that 4-tributyltin furo-
pyridines and 5-tributyltin pyranopyridines would give
access to further diversity onto the pyridine ring as some
sensitive, or difficult to obtain coupling partners could
also be introduced easily.
The tin-substituted triazine derivatives required for the
cycloaddition were prepared by a two-step procedure.
First, tri-n-butyltin was introduced by transmetallation of
the respective terminal alkynes (n-BuLi, Bu3SnCl, THF,
–78 °C). Deprotonation of the hydroxyl group of 26–27
was performed using NaH followed by addition of 1,2,4-
triazine 5 in THF at room temperature to afford the ex-
pected derivatives 28 and 29 in good yields. Subsequent
cycloaddition reaction of stannyl derivatives 28 and 29
was carried out under microwave irradiation in a sealed
tube under our optimal conditions to yield disubstituted
heterocycles 30 and 31 in 50% and 40%, respectively
(Scheme 4).
Acknowledgment
The authors thank Dr. J.-C. Frison for fruitful discussions.
References and Notes
(1) (a) Boger, D. L. Chem. Rev. 1986, 86, 781. (b) Boger, D. L.
Tetrahedron 1983, 39, 2869. (c) Sauer, J.; Heldmann, D. K.;
Hetzenegger, J.; Krauthan, J.; Sichert, H.; Schuster, J. Eur.
J. Org. Chem. 1998, 2885.
(2) (a) Hajbi, Y.; Suzenet, F.; Khouili, M.; Lazar, S.;
Guillaumet, G. Tetrahedron 2007, 63, 8286. (b) Lindsley,
C. W.; Layton, M. E. In Science of Synthesis, Vol. 17;
Weinreb, S. M., Ed.; Thieme: NewYork, 2003, 357–447.
(c) Branowska, D.; Ostrowski, S.; Rykowski, A. Chem.
Pharm. Bull. 2002, 50, 463. (d) Sauer, J.; Heldmann, D. K.;
Pabst, G. R. Eur. J. Org. Chem. 1999, 313. (e) Taylor,
E. C.; Macor, J. E.; French, L. G. J. Org. Chem. 1991, 56,
1807. (f) Taylor, E. C.; Macor, J. E. J. Org. Chem. 1987, 52,
4280. (g) Taylor, E. C.; Macor, J. E. Tetrahedron Lett. 1986,
To demonstrate the utility of pyridines 30 and 31, Stille
couplings with 3-bromopyridine were carried out. In
DMF at 90 °C for 4 hours, using 5% mol of Pd(PPh3)4 and
LiCl, the expected products 32 and 33 were formed in
71% and 68% yield, respectively (Scheme 5).9
In conclusion, we have demonstrated that the intramolec-
ular Diels–Alder reaction is a powerful methodology for
Synlett 2009, No. 1, 92–96 © Thieme Stuttgart · New York

LETTER
27, 2107. (h) Taylor, E. C.; Macor, J. E. J. Org. Chem. 1989,
Dihydrofuro- and Dihydropyrano[2,3-b]pyridines
4-Fur-2-yl-2,3-dihydrofuro[2,3-b]pyridine (14)
95
54, 4984. (i) Taylor, E. C.; Pont, J. L. J. Org. Chem. 1987,
52, 4287. (j) Seitz, G.; Görge, L.; Dietrich, S. Tetrahedron
Lett. 1985, 26, 4355. (k) Buysens, K. J.; Vandenberghe,
D. M.; Toppet, S. M.; Hoornaert, G. J. Tetrahedron 1995,
51, 12463. (l) Taylor, E. C.; Macor, J. E. Tetrahedron Lett.
1986, 27, 431. (m) Taylor, E. C.; Macor, J. E.; Pont, J. L.
Tetrahedron 1987, 43, 5145. (n) Taylor, E. C. Bull. Soc.
Chim. Belg. 1988, 97, 599. (o) Haenel, F.; John, R.; Seitz,
G. Arch. Pharm. 1992, 325, 349. (p) Frissen, A. E.;
Marcelis, A. T. M.; Buurman, D. G.; Pollmann, C. A. M.;
van der Plas, H. C. Tetrahedron 1989, 45, 5611. (q) Seitz,
G.; Dietrich, S.; Gorge, L.; Richter, J. Tetrahedron Lett.
1986, 27, 2747. (r) Seitz, G.; Dietrich, S. Arch. Pharm.
1985, 318, 1048. (s) Seitz, G.; Dietrich, S. Arch. Pharm.
985, 318, 1051. (t) Lipińska, T.; Branowska, D.; Rykowski,
A. Chem. Heterocycl. Compd. 1999, 35, 334.
Yield 74%, as a yellow solid; mp 93–95 °C. IR (KBr): 2971,
1605, 1451, 1229, 1125, 1025, 807 cm–1. 1H NMR (250
MHz, CDCl3): d = 7.97 (d, J = 5.3 Hz, 1 H), 7.56 (t, J = 1.2
Hz, 1 H), 7.05 (d, J = 5.3 Hz, 1 H), 6.74 (d, J = 3.4 Hz, 1 H),
6.56 (dd, J = 1.2, 3.4 Hz, 1 H), 4.65 (t, J = 8.4 Hz, 2 H), 3.42
(t, J = 8.4 Hz, 2 H). 13C NMR (62.9 MHz, CDCl3): d = 169.5
(C), 151.0 (C), 146.8 (CH), 143.7 (CH), 135.1 (C), 113.4
(C), 112.0 (CH), 111.5 (CH), 110.5 (CH), 68.8 (CH2), 29.1
(CH2). MS: m/z [M + 1] = 188. HRMS: m/z calcd for
C11H10NO2 [M + 1]+: 188.0694; found: 188.0704.
(7) General Procedure for the Stille Cross-Coupling
Reaction for Compounds 18–21
To a suspension of freshly prepared Pd(PPh3)4 (25 mg, 0018
mmol) and LiCl (42 mg, 0.99 mmol) in dry DMF was added
a solution of compounds 14–17 (0.36 mmol) and tributyl-2-
propenylstannane (169 mL, 0.54 mmol) in dry DMF under
argon. After 2–3 h (see Table 3) under reflux at 90 °C, the
reaction mixture was cooled to r.t. and quenched with brine
(10 mL). The aqueous layer was extracted with EtOAc
(2 × 20 mL), the organic phase were collected, dried over
MgSO4, and the solvents were removed under reduced
pressure. Flash column chromatography (eluent: PE–
EtOAc, 9:1) of the crude gave the desired products 18–21.
4-Allyl-2,3-dihydrofuro[2,3-b]pyridine (23)
(3) (a) Sammes, P. G.; Taylor, J. B. Comprehensive Medicinal
Chemistry, Vol. 6; Pergamon Press: Oxford, 1990.
(b) Lochead, A.; Jegham, S.; Galli, F.; Gallet, T.
WO 9842713, 1998; Chem. Abstr. 1998, 672553.
(c) Van Lommen, G. R. E.; Fernandez-Gadea, F. J.; Andres-
Gil, J. I.; Matesanz-Ballesteros, M. E. WO 9505381, 1995;
Chem. Abstr. 1995, 557282. (d) Comoy, C.; Marot, C.;
Podona, T.; Baudin, M. L.; Morin-Allory, L.; Guillaumet,
G.; Pfeiffer, B.; Caignard, D. H.; Renard, P.; Rettori, M. C.;
Adam, G.; Guardiola-Lemaitre, B. J. Med. Chem. 1996, 39,
4285. (e) Podona, T.; Guardiola-Lemaitre, B.; Caignard,
D.-H.; Adam, G.; Pfeiffer, B.; Renard, P.; Guillaumet, G.
J. Med. Chem. 1994, 37, 1779.
Yield 62%, as a yellow oil. IR (KBr): 2976, 2906, 1639,
1608, 1588, 1227 cm–1. 1H NMR (250 MHz, CDCl3): d =
7.90 (d, J = 5.3 Hz, 1 H), 6.62 (d, J = 5.3 Hz, 1 H), 5.95–5.79
(m, 1 H), 5.16–5.03 (m, 2 H), 4.60 (t, J = 8.4 Hz, 2 H), 3.30
(d, J = 6.6 Hz, 2 H), 3.17 (t, J = 8.4 Hz, 2 H). 13C NMR (62.9
MHz, CDCl3): d = 168.8 (C), 146.7 (CH), 146.3 (C), 134.0
(CH), 118.3 (C), 117.2 (CH2), 117.1 (CH), 68.8 (CH2), 37.3
(CH2), 26.8 (CH2). MS: m/z [M + 1] = 162. HRMS: m/z
calcd for C10H12NO [M + 1]+: 162.0906; found: 1162.0919.
(8) General Procedure for the Sonogashira Cross-Coupling
Reaction for Compounds 22–25
(4) Li, L.-S.; Wu, Y.-L. Tetrahedron Lett. 2002, 43, 2427.
(5) General Procedure for the Intramolecular Inverse-
Electron-Demand Diels–Alder Reaction for Compounds
10–13
Bromoalkyne 5, 6 or 8, 9 (0.33 mmol) was dissolved in
chlorobenzene (2 mL) and heated at 180–200 °C under
microwave irradiation (3–6 bar of pressure can be involved).
The reaction was monitored by TLC (for reaction time and
temperature, see Table 1). After complete conversion of the
starting material, the reaction was purified by chromatog-
raphy (eluent: PE–EtOAc, 8:2) to give the desired products
10–13.
A solution of the aryl bromide 12 or 13 (1.11 mmol) in anhyd
ethylene glycol dimethyl ether (2.0 mL) was treated with the
appropriate alkyne (1.11 mmol) and Et3N (3 mL). After 5
min, CuI (0.021 g, 0.11 mmol) and Pd(PPh3)2Cl2 (0.04 mg,
0.06 mmol) were added. The mixture was then stirred
vigorously at 60 °C and monitored by TLC. After 24 h, the
mixture was diluted with EtOAc and filtered through Celite.
The filtrate was washed with brine, and dried over MgSO4,
evaporated and purified by column chromatography (eluent:
PE–EtOAc, 9:1) to give the corresponding compounds 22–
25.
4-Bromo-2,3-dihydrofuro[2,3-b]pyridine (10)
Yield 82%, as a colorless oil. IR (KBr): 3000, 2908, 1577,
945, 713, 698, 614 cm–1. 1H NMR (250 MHz, CDCl3): d =
7.78 (d, J = 5.6 Hz, 1 H), 6.91 (d, J = 5.6 Hz, 1 H), 4.64 (t,
J = 8.8 Hz, 2 H), 3.23 (t, J = 8.8 Hz, 2 H). 13C NMR (62.9
MHz, CDCl3): d = 168.4 (C), 147.2 (CH), 129.9 (C), 121.6
(C), 119.8 (CH), 68.4 (CH2), 29.2 (CH2). MS: m/z [M + 1] =
200 (for 79Br) and 202 (for 81Br). HRMS: m/z calcd for
C7H7NO79Br [M + 1]+: 199.9709; found: 199.9709.
(6) General Procedure for the Suzuki Cross-Coupling
Reaction for Compounds 14–17
7-Phenyl-4-[2-(trimethylsilyl)ethynyl]-3,4-dihydro-2H-
pyrano[2,3-b]pyridine (25)
Yield 44%, as a dark oil. IR (KBr): 3049, 2248, 1580, 1428,
1352, 1233, 904, 742 cm–1. 1H NMR (250 MHz, CDCl3):
d = 7.96 (d, J = 8.2 Hz, 2 H), 7.43–7.33 (m, 4 H), 4.34 (t,
J = 5.2 Hz, 2 H), 3,30 (t, J = 6.5 Hz, 2 H), 2.06 (m, 2 H), 0.26
(s, 9 H). 13C NMR (62.9 MHz, CDCl3): d = 161.1 (C), 153.8
(C), 138.2 (C), 133.5 (C), 129.0 (CH), 128.6 (CH), 126.7
(CH), 117.6 (C), 116.4 (CH), 103.7 (C), 100.9 (C), 67.3
(CH2), 23.6 (CH2), 21.8 (CH2), –0.01 (CH3). MS: m/z [M +
1] = 308. HRMS: m/z calcd for C19H22NOSi [M + 1]+:
308.1468; found: 308.1471.
A solution of compounds 10–13 (0.73 mmol) in ethylene
glycol dimethyl ether (5 mL, freshly distilled and degassed)
under argon was treated with furan-2-boronic acid. A
solution of Na2CO3 (154 mg, 1.45 mmol) in H2O (2.5 mL)
was added before adding Pd(PPh3)4 (42 mg, 0.036 mmol),
and the mixture was stirred vigorously at 75 °C and
monitored by TLC (for reaction time, see Table 2). After
complete conversion of the starting material, the mixture
was diluted with EtOAc and filtered through Celite. The
filtrate was washed with brine, dried over MgSO4, evapo-
rated, and purified by column chromatography (eluent:
PE–EtOAc) to give the corresponding compounds 14–17.
(9) General Procedure for the Stille Reaction with
3-Bromopyridine
Compounds 32 and 33 were prepared in 70% yield,
according to the procedure used for the synthesis of 18–21.
The purification was carried out by flash chromatography
over SiO2 (eluent: PE–EtOAc, 8:2 to 6:4).
Synlett 2009, No. 1, 92–96 © Thieme Stuttgart · New York

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Y. Hajbi et al.
LETTER
7-Phenyl-5-pyrid-3-yl-3,4-dihydro-2H-pyrano[2,3-
b]pyridine (33)
Yield 68%, as a clear yellow oil. IR (KBr): 3160, 2970,
2253, 1574, 1444, 1002, 906, 740 cm–1. 1H NMR (250 MHz,
CDCl3): d = 8.64 (s, 1 H), 8.63 (d, J = 1.2 Hz, 1 H), 8.00 (d,
J = 6.5 Hz, 2 H), 7.68 (dd, J = 1.2 Hz, J¢ = 5.7 Hz, 1 H),
7.43–7.23 (m, 4 H), 7.23 (s, 1 H), 4.40 (t, J = 5.0 Hz, 2 H),
2.67 (t, J = 6.2 Hz, 2 H), 2.00–1.94 (m, 2 H). 13C NMR (62.9
MHz, CDCl3): d = 161.3 (C), 154.3 (C), 149.5 (CH), 149.3
(CH), 148.8 (C), 138.3 (C), 136.0 (CH), 134.7 (C), 129.1
(CH), 128.7 (CH), 126.8 (CH), 123.4 (CH), 114.9 (C), 113.6
(CH), 67.3 (CH2), 23.8 (CH2), 22.0 (CH2). MS: m/z [M +
1] = 289. HRMS: m/z calcd for C19H17N2O [M + 1]+:
289.1350; found: 289.1341.
Synlett 2009, No. 1, 92–96 © Thieme Stuttgart · New York

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