Polysubstituted 2,3-dihydrofuro[2,3-b]pyridines and 3,4-dihydro-2H-pyrano[2,3-b]pyridines via microwave-activated inverse electron demand Diels-Alder reactions

Article abstract of DOI:10.1016/j.tet.2007.05.112

Polysubstituted 2,3-dihydrofuro[2,3-b]pyridines and 3,4-dihydro-2H-pyrano[2,3-b]pyridines have been synthesized from 1,2,4-triazines using the inverse electron Diels-Alder reaction. For this purpose, 3-methylsulfanyl-1,2,4-triazines were reacted with seve

Full text of DOI:10.1016/j.tet.2007.05.112

Tetrahedron 63 (2007) 8286–8297
Polysubstituted 2,3-dihydrofuro[2,3-b]pyridines and 3,4-dihydro-
2H-pyrano[2,3-b]pyridines via microwave-activated inverse
electron demand Diels–Alder reactions
b
c
a,
Youssef Hajbi,a,b Franck Suzenet,a, Mostafa Khouili, Said Lazar and Gerald Guillaumet
*
*
ꢀ
a
´
Institut de Chimie Organique et Analytique (ICOA), UMR-CNRS 6005, University of Orleans, France
b
´
Laboratoire de Chimie Organique et Analytique, University Cadi-Ayyad, Beni-Mellal, Morocco
cLaboratoire de Biochimie, Environnement et Agroalimentaire, University of Hassan II-Mohammedia, Morocco
Received 4 April 2007; revised 22 May 2007; accepted 25 May 2007
Available online 2 June 2007
Abstract—Polysubstituted 2,3-dihydrofuro[2,3-b]pyridines and 3,4-dihydro-2H-pyrano[2,3-b]pyridines have been synthesized from 1,2,4-
triazines using the inverse electron Diels–Alder reaction. For this purpose, 3-methylsulfanyl-1,2,4-triazines were reacted with several nucleo-
philes allowing the formation of appropriately substituted alkynes to undergo the intramolecular inverse electron demand Diels–Alder
reaction. Sealed-tube microwave activation of the cycloaddition reaction has proved to be very efficient and allowed shorter reaction times.
This strategy enabled an efficient synthesis of 3-hydroxy-2,3-dihydrofuro[2,3-b]pyridines and 4-hydroxy-3,4-dihydro-2H-pyrano[2,3-b]-
pyridines with several points of diversity on the bicyclic scaffold.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
In the course of our studies on the synthesis of serotoninergic
ligands, we were interested in the synthesis of 2,3-dihydro-
furo[2,3-b]pyridines and 3,4-dihydro-2H-pyrano[2,3-b]-
pyridines. Those heterocycles, when substituted at
positions 3 and 4, respectively, on the non-aromatic ring,
were not much studied although they may have biological
interest due to their structural similarity to quinolines,
substituted pyridines, and chromanes.11 Looking at the liter-
ature,12 only few syntheses were reported. In the last decade,
with regards to dihydro[2,3-b]pyranopyridine derivatives,
8-azachromanones13 were used as precursor of 4-hydr-
oxypyrano[2,3-b]pyridine.14 Synthesis of pyranopyridines
via a LiCl mediated palladium-catalyzed15 or zirconium-
mediated16 cyclization as well as an approach using
thermal[3,3]sigmatropic rearrangement were mentioned.17
For dihydrofuropyridine derivatives, Shiotani et al. dealt
with some examples in the course of their studies on the
preparation and reactivity of furopyridines.18 Few other
syntheses were described19 and surprisingly, as far as we
know and despite the tremendous potential of the inverse
electron demand Diels–Alder strategy, only basic 2,3-
dihydrofuro[2,3-b]pyridines and 3,4-dihydro-2H-pyrano-
[2,3-b]pyridines were reported using this cycloaddition
strategy.3a–c,8a,20
Inverse electron demand Diels–Alder reactions of heterocy-
clic azadienes with electron-rich dienophiles have received
considerable attention.1 Among all the electron-deficient
heteroaromatic azadiene studied, we were interested in the
use of 1,2,4-triazine as part of our on going research on
this heterocycle.2 Many electron-rich dienophiles such as
olefins,3 enamines,4 indoles,5 pyrroles,6 imidazoles,7 ni-
triles8 or alkynes9 proved to be very efficient. Inverse elec-
tron demand Diels–Alder reaction with 1,2,4-triazines, in
fact, consist in a Diels–Alder/retro Diels–Alder (with nitro-
gen exclusion) sequence followed by an extra elimination/
aromatization step in the case of ‘alkenyl’ dienophiles.
When enamines were generated in situ as dienophiles, Tay-
lor and Raw have recently reacted the dihydropyridine inter-
mediate in a cascade reaction with an internal dienophile4d
and described the one-pot synthesis of highly substituted
pyridines, employing microwave irradiation or the tethered
imine–enamine methodology.4c,4g This cycloaddition with
1,2,4-triazines proved to be valuable fundamental reactions
for the construction of various heterocyclic compounds.10
* Corresponding authors. Tel.: +33 2 38 49 45 80; fax: +33 2 38 41 72 81
(F.S.); tel.: +33 2 38 41 73 54; fax: +33 2 38 41 72 81 (G.G.); e-mail
addresses: franck.suzenet@univ-orleans.fr; gerald.guillaumet@univ-
orleans.fr
At this stage, we thought that using judiciously functional-
ized 1,2,4-triazines with an alkyne moiety as dienophile,
could be a very potent synthetic pathway to polysubstituted
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.112

Y. Hajbi et al. / Tetrahedron 63 (2007) 8286–8297
8287
2,3-dihydrofuro[2,3-b]pyridines and 3,4-dihydro-2H-pyr-
ano[2,3-b]pyridines allowing several points of diversity.
Unfortunately, when refluxing 5 in the same experimental
conditions, i.e., in chlorobenzene (134 ꢀC) for 48 h, only
the starting material was recovered (Table 1, entry 1). This
result is in accordance with Taylor comments about the ne-
cessity to use more drastic cyclization conditions, probably
due to reduced ‘entropic assistance’.20c However, to avoid
degradation at higher temperature, we turned to microwave
activation.21 Indeed, this technology was applied to 1,2,4-
triazines synthesis22 and inverse electron demand Diels–
Alder reaction with alkenyl.4c,23 Thus, alkynol 5 was care-
fully heated in a sealed tube (see Section 3) at 220 ꢀC for
2 h under microwave irradiation to afford the more challeng-
ing 4-hydroxy-7-phenyl-3,4-dihydro-2H-pyrano[2,3-b]pyri-
dine 7 with an excellent yield of 93% (Table 1, entry 3).
Those microwave benefits (i.e., higher reaction temperature
and increased kinetic) are undeniable. Indeed, 5 did not react
in refluxing chlorobenzene (vide infra), and at higher tem-
perature in refluxing dichlorobenzene (Table 1, entry 2) or
in a sealed tube in chlorobenzene at 220 ꢀC (Table 1, entry
4), the cycloaddition did occur in 48 h with 72 and 90%
yields, respectively. Expected that the limiting step might
be the inverse electron demand Diels–Alder reaction com-
pared to the nitrogen extrusion in the retro Diels–Alder
step, we were curious to evaluate if the former cycloaddition
could be activated at high pressure. Indeed, few cases of
hyperbaric intramolecular Diels–Alder cycloadditions
were described. The results show limited but consistent yield
improvement.24 Thus, 5 was reacted in dichloromethane at
11.3 kbar for 48 h at room temperature. The starting material
was completely recovered indicating that pressure has no
effect on this type of cycloaddition.
2. Results and discussion
2.1. Synthesis of 3-hydroxy-2,3-dihydrofuro[2,3-b]-
pyridines and 4-hydroxy-3,4-dihydro-2H-pyrano-
[2,3-b]pyridines
Our strategy was first based on the functionalization of
the 1,2,4-triazine ring at position C-3 by nucleophilic
substitution with different acetylenic alkoxide. Thus, the
3-methylsulfonyl-1,2,4-triazine 1 was synthesized in agree-
ment with reported procedure10b from phenylglyoxal and
S-methylthiosemicarbazide followed by MCPBA oxidation
(Scheme 1).
N
S
NH2
NH2
N
a, b, c
HN
Ph
N
1
SO2Me
Scheme 1. (a) MeI, EtOH, reflux, 3 h (96%); (b) phenylglyoxal, Na2CO3,
H2O, 5 ꢀC, 6 h (82%); (c) MCPBA, CH2Cl2, rt, 4 h (87%).
In Scheme 2, nucleophilic displacement of methylsulfinate
from 1 with the sodium salt of allylic alcohol (n¼0) and ho-
moallylic alcohol (n¼1) afforded the 3-(3-propenyloxy)-
1,2,4-triazine 2 and 3-(4-butenyloxy)-1,2,4-triazine 3,
respectively. Double bond ozonolysis in dichloromethane
at ꢁ78 ꢀC gave the corresponding aldehyde, which reacts
with 2 equiv of ethynylmagnesium bromide in anhydrous
toluene. The resulting alkynols 4 and 5 were isolated in 61
and 72% yield over two steps.
Table 1. Cycloaddition activation conditions
OH
N
N
OH
solvent
conditions
Ph
N
O
Ph
N
O
7
N
N
N
5
( )n
( )n
N
, NaH
N
HO
THF, 2 h, rt
Ph
N
SO2Me
Ph
O
Entry Experimental
conditions
Solvent
T
Reaction Yield
(%)
(ꢀC) time (h)
2 n = 0 (81%)
3 n = 1 (83%)
1
1
2
3
Reflux
Reflux
Chlorobenzene 134
Dichlorobenzene 178
48
48
2
0
72
93
N
(i) O3, CH2Cl2
-78 °C, Me2S
N
OH
( )n
Microwaves
(sealed tube)
Chlorobenzene
220
Ph
N
O
(ii)
MgBr
4
Classical heat Chlorobenzene
(sealed tube)
220
48
90
4 n = 0 (61%)
5 n = 1 (72%)
1 h, toluene,
-30 °C, rt
Scheme 2. Synthesis of alkynols 4 and 5.
Improved experimental conditions were then applied to
compound 4. In this case, microwave heating at 220 ꢀC for
only 45 min (in contrast to 12 h in classical thermal condi-
tions) was sufficient to isolate the cycloadduct 6 in 91%
yield (Scheme 4).
Following the experimental procedure described by Taylor
and Macor,20c the triazine 4 was engaged in an intramole-
cular cycloaddition in chlorobenzene at reflux for 12 h to
give the novel 3-hydroxy-6-phenyl-2,3-dihydrofuro[2,3-b]-
pyridine 6 in excellent yield (Scheme 3).
OH
N
N
OH
( )n
OH
chlorobenzene
microwaves,
220 °C
n = 0 (45 min)
n = 1 (2 h)
N
N
( )n
Ph
N
O
chlorobenzene
Ph
N
O
Ph
N
O
reflux, 12 h
O
6 n = 0 (91%)
7 n = 1 (93%)
4 n = 0
5 n = 1
Ph
N
OH
4
6 (93%)
Scheme 3. Synthesis of compound 6 via an intramolecular inverse electron
demand Diels–Alder.
Scheme 4. Intramolecular inverse electron demand Diels–Alder reaction
under microwave irradiation.

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Y. Hajbi et al. / Tetrahedron 63 (2007) 8286–8297
Table 2. Sonogashira cross-coupling reaction
2.2. Synthesis of 4-substituted-2,3-dihydrofuro[2,3-b]-
pyridines and 5-substituted-3,4-dihydro-2H-
pyrano[2,3-b]pyridines
Entry
1
ArX
Product
Yielda (%)
79
Br
Br
10, n¼0
In order to allow functionalization on the final pyridine ring,
to extend diversity and to evaluate the reactivity of bis-
substituted alkynes towards the inverse electron demand
Diels–Alder reaction, we decided to prepare a series of
aryl- and heteroarylalkynes (10–19) via the sequence de-
scribed in Scheme 5.
N
N
2
3
4
5
15, n¼1
11, n¼0
16, n¼1
12, n¼0
74
78
97
81
S
S
I
I
N
N
N
( )n
HO
N
N
( )n
Me
NaH, THF
1 h, rt
Ph
N
SO2Me
Ph
O
8 n= 0 (86%)
9 n= 1 (74%)
1
I
I
Me
ArX
N
N
CuI, Pd(PPh3)2Cl2
6
7
8
9
17, n¼1
13, n¼0
18, n¼1
14, n¼0
76
71
62
73
( )n
Ar
Et3N, DME, 60 °C
1 h
Ph
N
O
10-19
NO2
NO2
OMe
Scheme 5. Synthesis of arylalkynes 10–19.
Br
Br
I
The methylsulfone 1 was substituted by propargylic alcohol
(n¼0) and homopropargylic alcohol (n¼1) in the presence
of NaH in THF. The resulting terminal alkynes 8 and 9
were then engaged in a Sonogashira cross-coupling reaction.
Thus, treating 4-bromopyridine in DMF with Pd(PPh3)2Cl2
(5 mol %), CuI, and Et3N, allowed the formation of the cor-
responding arylalkynes 10 and 15 in, respectively, 46 and
42% yields. In order to improve these moderate yields, the
same reaction was performed with DME as solvent. The
coupled products 10 and 15 were isolated in 79 and 74%
yields (Table 2, entries 1 and 2). With these optimized exper-
imental conditions, 2-iodothiophene (Table 2, entries 3 and
4), 4-iodotoluene (Table 2, entries 5 and 6), p-bromonitro-
benzene (Table 2, entries 7 and 8), and p-iodomethoxybenz-
ene (Table 2, entries 9 and 10) were reacted in DME with
Pd(PPh3)2Cl2 (5 mol %), CuI, and Et3N, to afford the corre-
sponding arylalkynes (10–19) in good yields (62–97%). In-
verse electron demand Diels–Alder reactions were then
carried out under the experimental conditions described
above. As illustrated in Table 3, 4-substituted-2,3-dihydro-
furo[2,3-b]pyridines (20–24) were obtained in very good
yields (82–99%) at 180 ꢀC. In the case of 5-substituted-
3,4-dihydro-2H-pyrano[2,3-b]pyridines (25–29) the pres-
ence of the aryl moiety generate longer reaction times and
higher temperatures (240 ꢀC vs 180 ꢀC). Nevertheless, de-
sired heterocycles were isolated in 72–84% yields. It is note-
worthy that even with electron-deficient hetaryl (Table 3,
entries 1 and 2) or electron-withdrawing group on the aryl
moiety (Table 3, entries 7 and 8) linked to the alkyne, the
reaction proceeds in good yields.
OMe
10
19, n¼1
70
I
a
Yield of pure isolated product.
reaction carried out with the alkynol 5 gave coupling com-
pounds 34–37 in better yields (Table 4, entries 2, 4, 6, and 8).
The cycloaddition reaction was first undertaken with alkyne
30 under microwave irradiation in a sealed tube. Under our
optimal experimental conditions (i.e., 180 ꢀC for the five-
membered ring formation) the trisubstituted heterocycle 38
was isolated in 40% yield (Table 5, entry 1). Only traces
Table 3. Intramolecular inverse electron demand Diels–Alder reactions
under microwave irradiation
Ar
N
N
Chlorobenzene
( )n
( )n
Ph
N
O
microwaves, T°C
Ph
N
O
Ar
10-19
20-29
Entry
Aryl
Product
T (ꢀC)/t (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
Pyrid-4-yl
Pyrid-4-yl
Thien-2-yl
Thien-2-yl
p-Tolyl
p-Tolyl
p-Nitrophenyl
p-Nitrophenyl
p-Methoxyphenyl
p-Methoxyphenyl
20, n¼0
180/3.5
240/8
180/2.5
240/8
180/2.5
240/6
180/4
240/8
180/3
240/6
94
72
82
72
99
84
74
67
83
79
With this efficient approach in hand, we investigated what
would be the cumulative effect of both alcohol and aryl moi-
eties as a new way toward the synthesis of polysubstituted
dihydrofuro- and dihydropyranopyridines. Starting from al-
kynol 4, the Sonogashira cross-coupling reaction was per-
formed using the optimized experimental conditions (vide
supra). Surprisingly, the resulting compounds 30–33 were
isolated in moderate yields (Table 4, entries 1, 3, 5, and 7)
without any traces of starting material. However, the same
25, n¼1
21, n¼0
26, n¼1
22, n¼0
27, n¼1
23, n¼0
28, n¼1
24, n¼0
29, n¼1
a
Yield of pure isolated product.

Y. Hajbi et al. / Tetrahedron 63 (2007) 8286–8297
8289
Table 4. Sonogashira cross-coupling reactions from alkynols 4 and 5
of the corresponding dehydrated compound were observed.
In order to minimize degradation products, the reaction was
done at 160 ꢀC for 1.5 h, 38 was isolated in only 31% yield
with traces of dehydrated compound. From these results,
it appears that reactions carried out at lower temperature
need longer reaction times and consequently increase the
amount of degradation products. Using the former con-
ditions, this approach was then extended to other aryl
substituents as reported in Table 5. In all cases, dihydrofuro-
pyridine derivatives were isolated in moderate to good yields
with traces of the dehydrated compounds.
Ar
N
ArX, CuI,
N
N
N
Pd(PPh3)2Cl2
N
( )n
Ph
N
O
OH
Et3N, DME,
60 °C
( )n
Ph
O
OH
4 n= 0
5 n= 1
30-33
34-37
Entry
1
ArX
Product
t (h)
Yielda (%)
53
S
I
I
30, n¼0
1
3
S
2
3
34, n¼1
31, n¼0
70
49
We then turned our attention to alkynol 34. We were pleased
to obtain 40% yield of the dihydropyranopyridine 42 at
200 ꢀC (optimal conditions for the six-membered ring for-
mation). Unfortunately, we have noted the presence of
16% of the dehydrated compound 45. To avoid this side re-
action, the cycloaddition reaction was carried out at lower
temperature. No improvement was observed as the forma-
tion of 45 (5%) occurred whereas the starting material was
still present (26%) in the mixture (Table 6, entry 2). The
same result was observed with alkyne 36 (Table 6, entries
6 and 7). At higher temperature, 34 and 35 only gave the de-
hydrated products 45 and 46, respectively (Table 6, entry 5).
It is noteworthy that for the nitro derivative 37, only degrada-
tion products were observed (Table 6, entry 8). These two
last examples show that the nature of the substituents on
the aryl moiety have an impact on the efficiency of the cyclo-
addition. In all cases, the dehydration side reaction seems to
occur after the inverse electron demand Diels–Alder reaction
as we never observed formation of any enyne derivatives.
Me
1
3
1
I
I
Me
4
5
35, n¼1
32, n¼0
81
55
OMe
I
OMe
NO2
6
7
36, n¼1
33, n¼0
1
1
64
42
I
Br
NO2
8
37, n¼1
4
47
Br
a
Yield of pure isolated product.
Table 5. Inverse electron demand Diels–Alder reactions from alkynols 30–33
Ar
N
Ar
N
OH
N
N
Ar
chlorobenzene
microwaves
+
O
Ph
N
O
O
Ph
Ph
OH
30-33
dehydrated products
38-41
Entry
Starting alkynol (Ar)
T (ꢀC)/t (min)
Alcohols (yield %)a
Dehydrated product
1
2
3
4
30 (Thien-2-yl)
31 (p-Tolyl)
32 (p-Methoxyphenyl)
33 (p-Nitrophenyl)
180/45
180/60
180/45
180/90
38 (40)
39 (40)
40 (82)
41 (34)
Traces
Traces
Traces
Traces
a
Yield of pure isolated product.
Table 6. Inverse electron demand Diels–Alder reactions from alkynols 34–37
Ar OH
Ar
N
N
N
OH
chlorobenzene
microwaves
+
Ph
N
O
Ph
N
O
Ph
O
Ar
dehydrated products 45-47
34-37
42-44
Entry
Starting alkynol (Ar)
T (ꢀC)/t (h)
Alcohol (yield %)a
Dehydrated product (yield %)a
Recovered starting material (yield %)a
1
2
3
4
5
6
7
8
34 (Thien-2-yl)
34 (Thien-2-yl)
34 (Thien-2-yl)
35 (p-Tolyl)
200/1
180/4.5
220/1
200/1.5
220/1
180/4.5
200/1
200/2
42 (40)
42 (21)
—
43 (39)
—
45 (16)
45 (5)
45 (66)
46 (14)
46 (51)
47 (5)
—
34 (26)
—
—
—
36 (50)
—
35 (p-Tolyl)
36 (p-Methoxyphenyl)
36 (p-Methoxyphenyl)
37 (p-Nitrophenyl)
44 (43)
44 (64)
47 (14)
Degradation
a
Yield of pure isolated product.

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Y. Hajbi et al. / Tetrahedron 63 (2007) 8286–8297
In this article, we have extended the efficiency of the inverse
electron demand Diels–Alder reaction to the synthesis of
highly substituted 2,3-dihydrofuro[2,3-b]pyridines and 3,4-
dihydro-2H-pyrano[2,3-b]pyridines. The developed ap-
proach allows a high diversity of substituent on the bicyclic
scaffold. Microwave activation has proven to be very effi-
cient as it allows an easy access to higher temperature with
shorter reaction time. Further studies to extend diversity
and to limit dehydration side reaction on these heterocycles
are underway.
6.26–6.11 (m, 1H), 5.43 (dd, J¼0.9 Hz, J0¼17.2 Hz, 1H),
5.36 (dd, J¼0.9 Hz, J0¼10.4 Hz, 1H), 5.13 (d, J¼5.6 Hz,
2H); 13C NMR (62.9 MHz, CDCl3) d 165.2 (C), 157.9 (C),
141.6 (CH), 141.5 (C), 132.8 (CH), 132.0 (C), 129.4 (CH),
127.8 (CH), 119.1 (CH2), 69.1 (CH2). HRMS calculated
for C12H11N3O 213.09021, found 213.0894.
3.2.2. 3-But-3-enyloxy-5-phenyl-1,2,4-triazine (3). Yield
83%, 0.80 g, as a yellow oil; IR (NaCl) cmꢁ1: 3018, 1640,
1518, 1446, 1218, 1078; 1H NMR (250 MHz, CDCl3)
d 9.25 (s, 1H), 8.01 (dd, J¼1.4 Hz, J0¼7.5 Hz, 2H), 7.98–
7.32 (m, 3H), 5.88–5.71 (m, 1H), 5.02 (dd, J¼1.6 Hz,
J0¼17.2 Hz, 1H), 4.95 (dd, J¼1.0 Hz, J0¼10.1 Hz, 1H),
4.47 (t, J¼6.9 Hz, 2H), 2.67 (q, J¼6.9 Hz, 2H); 13C NMR
(62.9 MHz, CDCl3) d 165.6 (C), 158.0 (C), 141.7 (CH),
134.1 (CH), 133.4 (C), 132.9 (CH), 129.6 (CH), 128.1
(CH), 117.8 (CH2), 68.0 (CH2), 33.5 (CH2). HRMS calcu-
lated for C13H13N3O 227.10586, found 227.1044.
3. Experimental
3.1. General
Microwave-assisted reactions were carried out in a Biotage
Initiator microwave synthesis instrument. Caution, the mi-
crowave apparatus has to be equipped with a safety pressure
shutoff. Experiments carried out on 0.3 mmol scale of tri-
azine in a 2–5 mL vial can generate 3–6 bars of pressure.
1H NMR and 13C NMR were recorded on a Bruker Avance
3.3. General procedure for the preparation of alkynols
4 and 5
1
DPX250 spectrometer (250.19 MHz H, 62.89 MHz 13C)
Ozone in oxygen was bubbled into a solution of alkene 2 or
3 (8.80 mmol) in 120 mL of CH2Cl2 and 10 mL of MeOH
at ꢁ78 ꢀC until the solution turned pale blue. Then, 40 mL
of dimethyl sulfide was added dropwise. The mixture was
allowed to warm to room temperature over 30 min. The
solvents were evaporated in vacuo. The residual oil
(10.90 mmol) was dissolved in anhydrous toluene (30 mL),
cooled to ꢁ30 ꢀC, and ethynylmagnesium bromide
(17.60 mmol, 0.5 M in tetrahydrofuran) was added dropwise
over a period of 15 min. After 1 h at ꢁ30 ꢀC, the reaction
mixture was quenched with a saturated aqueous solution of
ammonium chloride (60 mL). The separated aqueous layer
was extracted with CH2Cl2 (3ꢂ40 mL) and the combined
organic extracts were dried over MgSO4, evaporated, and
purified by chromatography with petroleum ether–ethyl ace-
tate (8:2), to give the corresponding alkynol 4 or 5.
using tetramethylsilane as the internal standard, multiplici-
ties were determined by the DEPT 135 sequence, chemical
shifts were reported in parts par million (ppm, d units). Cou-
pling constants were reported in units of hertz (Hz) if appli-
cable. Infrared (IR) spectra were obtained on Perkin–Elmer
Paragon 1000 PC FTIR. Infrared spectra were recorded us-
ing NaCl films or KBr pellets. Low-resolution mass spectra
(MS) were recorded on a Perkin–Elmer SCIEX API 3000
spectrometer. Melting points were determined in open capil-
lary tubes and are uncorrected. Flash chromatography was
performed on silica gel 60 (40–63 mesh). Thin layer chroma-
tography (TLC) was carried out on Merck silica gel 60F254
precoated plates. Visualization was made with ultraviolet
light. Reactions requiring anhydrous conditions were per-
formed under argon. Ethylene glycol dimethyl ether, toluene
and tetrahydrofuran were freshly distilled from sodium/
benzophenone under argon prior to use. Dichloromethane
was distilled from calcium hydride under argon prior to
use. Chemicals products were obtained from the following
sources: Aldrich and Acros.
3.3.1. 1-(5-Phenyl-1,2,4-triazin-3-yloxy)-but-3-yn-2-ol
(4). Yield 61%, 1.29 g, as a white solid; mp 130–132 ꢀC;
IR (KBr) cmꢁ1: 3450, 3260, 3019, 2881, 2121, 1598,
1
1470, 1215; H NMR (250 MHz, CDCl3) d 9.45 (s, 1H),
8.15 (dd, J¼1.6 Hz, J0¼8.1 Hz, 2H), 7.65–7.53 (m, 3H),
4.93 (br s, 1H), 4.77 (d, J¼5.3 Hz, 2H), 3.16 (d, J¼5.0 Hz,
OH), 2.55 (d, J¼2.2 Hz, 1H); 13C NMR (62.9 MHz,
CDCl3) d 165.3 (C), 158.4 (C), 142.1 (CH), 133.1 (CH),
132.9 (C), 129.5 (CH), 128.0 (CH), 80.7 (C), 74.9 (CH2),
71.5 (C), 61.1 (CH). HRMS calculated for C13H11N3O2
241.08513, found 241.0859.
3.2. General procedure for the preparation of alkenes
2 and 3
To a stirred suspension of NaH (0.22 g of 60% oil dispersion,
5.53 mmol) in dry THF (20 mL) under a nitrogen atmo-
sphere, was added the required alcohol (5.53 mmol) at
0 ꢀC. After 10 min, the triazine 1 (1 g, 4.25 mmol) was
added. Then, the mixture was warmed to room temperature
and monitored by TLC. After complete conversion of the
starting material, the reaction was quenched with 40 mL of
water and extracted with ethyl acetate (3ꢂ60 mL). The or-
ganic layer was dried over MgSO4, evaporated, and purified
by column chromatography (eluant: petroleum ether–ethyl
acetate, 8:2) to give the corresponding ether 2 or 3.
3.3.2. 5-(5-Phenyl-1,2,4-triazin-3-yloxy)-pent-1-yn-3-ol
(5). Yield 72%, 1.62 g, as a yellow solid; mp 92–94 ꢀC; IR
(KBr) cmꢁ1: 3304, 3013, 2891, 2220, 1542, 1420; 1H
NMR (250 MHz, CDCl3) d 9.42 (s, 1H), 8.15 (dd,
J¼1.8 Hz, J0¼7.5 Hz, 2H), 7.61–7.52 (m, 3H), 4.92–4.75
(m, 3H), 2.79 (d, J¼2.2 Hz, 1H, OH), 2.50 (d, J¼2.0 Hz,
1H), 2.31 (q, J¼6.9 Hz, 2H); 13C NMR (62.5 MHz,
CDCl3) d 165.4 (C), 158.1 (C), 141.6 (CH), 133.0 (C),
132.9 (CH), 129.5 (CH), 127.9 (CH), 84.2 (C), 73.5 (C),
65.1 (CH2), 59.3 (CH), 36.8 (CH2); m/z (M+1)¼256.
HRMS calculated for C14H13N3O2 255.10078, found
255.0999.
3.2.1. 3-Allyloxy-5-phenyl-1,2,4-triazine (2). Yield 81%,
0.73 g, as a yellow oil; IR (NaCl) cmꢁ1: 3062, 1914, 1648,
1550, 1188; H NMR (250 MHz, CDCl3) d 9.42 (s, 1H),
1
8.16 (dd, J¼1.2 Hz, J0¼7.1 Hz, 2H), 7.62–7.55 (m, 3H),

Y. Hajbi et al. / Tetrahedron 63 (2007) 8286–8297
8291
3.3.3. 6-Phenyl-2,3-dihydrofuro[2,3-b]pyridin-3-ol (6).
Compound 4 (0.1 g, 0.41 mmol) was dissolved in chloro-
benzene (2 mL), and was heated at 180 ꢀC under microwave
irradiation for 45 min. The solvent was removed in vacuo
and the residue was purified by chromatography with petro-
leum ether–ethyl acetate (4:6) to afford 6 (0.079 g, 91%
mp 85.5–88 ꢀC); IR (KBr) cmꢁ1: 3065, 3055, 2911, 2115,
1600, 1447; H NMR (250 MHz, CDCl3) d 9.41 (s, 1H),
1
8.19–8.15 (m, 2H), 7.63–7.52 (m, 3H), 4.72 (t, J¼6.4 Hz,
2H), 2.51–2.45 (m, 2H), 2.20–2.09 (m, 2H), 2.01 (t,
J¼2.5 Hz, 1H); 13C NMR (62.9 MHz, CDCl3) d 165.5 (C),
158.0 (C), 141.6 (CH), 133.9 (C), 132.9 (CH), 129.4 (CH),
127.9 (CH), 83.2 (C), 69.2 (CH), 67.2 (CH2), 27.8 (CH2),
15.3 (CH2); m/z (M+1)¼240.
yield), as a yellow solid; mp 111–113 ꢀC; IR (KBr) cmꢁ1
:
1
3258, 3017, 1605, 1576, 1413, 1214; H NMR (250 MHz,
CDCl3) d 7.87 (dd, J¼1.9 Hz, J0¼7.8 Hz, 2H), 7.61 (d, J¼
7.9 Hz, 1H), 7.47–7.39 (m, 3H), 7.19 (d, J¼7.9 Hz, 1H),
5.38–5.31 (m, 1H), 4.56 (dd, J¼6.9 Hz, J0¼10.7 Hz, 1H),
4.43 (dd, J¼2.8 Hz, J0¼10.7 Hz, 1H), 3.54 (d, J¼8.1 Hz,
OH); 13C NMR (62.9 MHz, CDCl3) d 168.1 (C), 157.8
(C), 138.4 (C), 135.8 (CH), 129.3 (CH), 128.7 (CH), 127.1
(CH), 119.5 (C), 114.0 (CH), 78.2 (CH2), 70.1 (CH); m/z
(M+1)¼214. Anal. Calcd for C13H11NO2+H2O (33%): C,
71.71; H, 5.32; N, 6.43. Found: C, 71.72; H, 4.94; N, 6.46.
3.5. General procedure for the Sonogashira cross-
coupling reaction (10–19 and 30–37)
A solution of the appropriate aryl halide (1.11 mmol) in
2.0 mL of anhydrous ethylene glycol dimethyl ether
was treated with alkynes 8 and 9 or alkynols 4 and 5
(1.11 mmol) and Et3N (3 mL). After 5 min, copper iodide
(0.021 g, 0.11 mmol) and bis(triphenylphosphine)-
palladium(II) dichloride (0.04 mg, 0.055 mmol) were
added. The mixture was then stirred vigorously at 60 ꢀC
and monitored by TLC. After complete conversion of the
starting material, the mixture was diluted with ethyl acetate
and filtered through Celite. The filtrate was washed with
brine, dried over MgSO4, evaporated, and purified by col-
umn chromatography to give the corresponding compounds
10–19 or 30–33.
3.3.4. 7-Phenyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-
ol (7). Compound 5 (0.1 g, 0.39 mmol) was dissolved in
chlorobenzene (2 mL), and was heated at 220 ꢀC under
microwave irradiation for 2 h. The solvent was removed
in vacuo and the residue was purified by chromatography
with petroleum ether–ethyl acetate (6:4) to afford 7
(0.082 g, 93% yield) as a red dark oil; IR (KBr) cmꢁ1
:
1
3405, 2960, 1734, 1599, 1473, 1060; H NMR (250 MHz,
CDCl3) d 7.98 (d, J¼7.4 Hz, 2H), 7.63 (d, J¼7.5 Hz, 1H),
7.45–7.36 (m, 3H), 7.27 (d, J¼7.5 Hz, 1H), 5.43 (t,
J¼4.4 Hz, 1H), 4.48–4.28 (m, 2H), 3.40 (s, 1H), 2.14–1.91
(m, 2H); 13C NMR (62.9 MHz, CDCl3) d 160.4 (C), 156.4
(C), 139.7 (CH), 138.3 (C), 129.2 (CH), 128.6 (CH), 127.0
(CH), 118.1 (C), 114.1 (CH), 63.3 (CH), 63.0 (CH2), 30.7
(CH2); m/z (M+1)¼228. Anal. Calcd for C14H13NO2: C,
73.99; H, 5.77; N, 6.16. Found: C, 73.60; H, 5.59; N, 6.24.
3.5.1. 5-Phenyl-3-(4-pyrid-4-ylbut-3-ynyloxy)-1,2,4-tri-
azine (10). Yield 79%, as a white solid; mp 118–120 ꢀC;
1
IR (KBr) cmꢁ1: 3015, 2200, 1598, 1366, 1214; H NMR
(250 MHz, CDCl3) d 9.45 (s, 1H), 8.52 (d, J¼5.8 Hz, 2H),
8.17 (dd, J¼1.6 Hz, J0¼7.5 Hz, 2H), 7.62–7.52 (m, 3H),
7.27 (d, J¼5.8 Hz, 2H), 4.80 (t, J¼6.9 Hz, 2H), 3.10 (t,
J¼6.9 Hz, 2H); 13C NMR (62.9 MHz, CDCl3) d 165.0 (C),
158.0 (C), 149.6 (CH), 141.8 (CH), 132.8 (CH), 131.5 (C),
129.3 (CH), 127.8 (CH), 127.7 (C), 125.8 (CH), 90.8 (C),
80.0 (C), 65.93 (CH2), 20.1 (CH2); m/z (M+1)¼303.
HRMS calculated for C18H14N4O 302.11676, found
302.1176.
3.4. General procedure for the preparation of alkynes
8 and 9
To a stirred suspension of NaH (0.22 g of 60% oil dispersion,
5.53 mmol) in dry THF (20 mL) under nitrogen atmosphere
was added the appropriated alcohol (5.53 mmol) at 0 ꢀC. Af-
ter 10 min, the triazine 1 (4.25 mmol) was added. The mix-
ture was then warmed to room temperature and monitored by
TLC. After complete conversion of the starting material, the
reaction was quenched with 40 mL of water and extracted
with ethyl acetate (3ꢂ60 mL). The organic layer was dried
over MgSO4, evaporated, and purified by column chromato-
graphy (eluant: petroleum ether–ethyl acetate, 8:2) to give
the corresponding alkene 8 or 9.
3.5.2. 5-Phenyl-3-(4-thien-2-ylbut-3-ynyloxy)-1,2,4-tri-
azine (11). Yield 78%, as a red oil; IR (KBr) cmꢁ1: 3015,
2060, 1542, 1022; H NMR (250 MHz, CDCl3) d 9.43 (s,
1
1H), 8.15 (d, J¼7.5 Hz, 2H), 7.61–7.55 (m, 3H), 7.20–
7.55 (m, 2H), 6.91 (dd, J¼3.8 Hz, J0¼5.1 Hz, 1H), 4.80 (t,
J¼7.0 Hz, 2H), 3.05 (t, J¼7.0 Hz, 2H); 13C NMR
(62.9 MHz, CDCl3) d 165.2 (C), 158.0 (C), 141.7 (CH),
133.0 (C), 132.8 (CH), 131.7 (CH), 129.4 (CH), 127.9
(CH), 126.8 (CH), 126.5 (CH), 123.4 (C), 89.4 (C), 75.6
(C), 66.2 (CH2), 20.4 (CH2); m/z (M+1)¼308. HRMS calcu-
lated for C17H13N3OS 307.07793, found 307.0764.
3.4.1. 3-But-3-ynyloxy-5-phenyl-1,2,4-triazine (8).20c
Yield 86%, 0.82 g, as a yellow solid; mp 103–105 ꢀC
(lit.25 mp 105–106.5 ꢀC); IR (KBr) cmꢁ1: 3227, 3096,
2980, 2241, 1597, 1413; 1H NMR (250 MHz, CDCl3)
d 9.43 (s, 1H), 8.19–8.16 (m, 2H), 7.61–7.53 (m, 3H), 4.74
(t, J¼7.0 Hz, 2H), 2.83 (dt, J¼2.9 Hz, J0¼7.0 Hz, 2H),
2.50 (t, J¼2.9 Hz, 1H); 13C NMR (62.9 MHz, CDCl3)
d 165.2 (C), 158.1 (C), 141.8 (CH), 133.1 (C), 132.9 (CH),
129.5 (CH), 127.9 (CH), 79.9 (C), 70.4 (CH2), 66.3 (CH),
19.5 (CH2); m/z (M+1)¼226.
3.5.3. 5-Phenyl-3-(4-p-tolylbut-3-ynyloxy)-1,2,4-triazine
(12). Yield 81%, as a red solid; mp 177–179 ꢀC; IR (KBr)
cmꢁ1: 3000, 2241, 1620, 1599, 1542, 1470; 1H NMR
(250 MHz, CDCl3) d 9.43 (s, 1H), 8.16 (dd, J¼0.9 Hz,
J0¼7.5 Hz, 2H), 7.61–7.51 (m, 3H), 7.29 (d, J¼7.8 Hz,
2H), 7.07 (d, J¼7.8 Hz, 2H), 4.78 (t, J¼7.2 Hz, 2H), 3.02
(t, J¼7.2 Hz, 2H), 2.32 (s, 3H); 13C NMR (62.9 MHz,
CDCl3) d 165.3 (C), 158.1 (C), 141.8 (CH), 138.1 (C),
133.1 (C), 132.9 (CH), 131.6 (CH), 129.5 (CH), 129.1
(CH), 128.0 (CH), 120.3 (C), 84.4 (C), 82.5 (C), 66.6
(CH2), 21.5 (CH3), 20.2 (CH2); m/z (M+1)¼316. HRMS
calculated for C20H17N3O 315.13716, found 315.1343.
3.4.2. 3-Pent-4-ynyloxy-5-phenyl-1,2,4-triazine (9).20c
Yield 74%, 0.75 g, as a yellow solid; mp 85–87 ꢀC (lit.25

8292
Y. Hajbi et al. / Tetrahedron 63 (2007) 8286–8297
3.5.4. 3-(4-(4-Nitrophenyl)but-3-ynyloxy)-5-phenyl-
1,2,4-triazine (13). Yield 71%, as a yellow solid; mp 154–
156 ꢀC; IR (KBr) cmꢁ1: 3165, 2256, 1537, 1463, 1339,
(C), 87.9 (C), 81.5 (C), 67.4 (CH2), 28.1 (CH2), 21.4
(CH3), 16.3 (CH2); m/z (M+1)¼330. HRMS calculated for
C21H19N3O 329.15281, found 329.1524.
1
1201; H NMR (250 MHz, CDCl3) d 9.45 (s, 1H), 8.17
(dd, J¼1.5 Hz, J0¼7.4 Hz, 2H), 8.13 (d, J¼9.1 Hz, 2H),
7.62–7.55 (m, 3H), 7.53 (d, J¼9.1 Hz, 2H), 4.82 (t,
J¼6.9 Hz, 2H), 3.09 (t, J¼6.9 Hz, 2H); 13C NMR
(62.9 MHz, CDCl3) d 165.2 (C), 158.2 (C), 147.0 (C),
142.0 (CH), 133.0 (CH), 133.0 (C), 132.5 (CH), 130.4 (C),
129.5 (CH), 128.0 (CH), 123.6 (CH), 91.5 (C), 80.9 (C),
66.1 (CH2), 20.4 (CH2); m/z (M+1)¼347. HRMS calculated
for C19H14N4O3 345.09877, found 345.0995.
3.5.9. 3-(5-(4-Nitrophenyl)pent-4-ynyloxy)-5-phenyl-
1,2,4-triazine (18). Yield 62%, as a green solid; mp 112–
114 ꢀC; IR (KBr) cmꢁ1: 3429, 3009, 2229, 1788, 1596,
1
1541, 1215; H NMR (250 MHz, CDCl3) d 9.42 (s, 1H,
H6), 8.18 (dd, J¼1.5, 7.8 Hz, 2H), 8.14 (d, J¼8.4 Hz, 2H),
7.58–7.51 (m, 3H), 7.49 (d, J¼8.4 Hz, 2H), 4.77 (t,
J¼5.9 Hz, 2H), 2.73 (t, J¼6.9 Hz, 2H), 2.31–2.20 (tt,
J¼5.9 Hz, J0¼6.9 Hz, 2H); 13C NMR (62.9 MHz, CDCl3)
d 165.4 (C), 158.1 (C), 146.8 (C), 141.7 (CH), 133.1 (C),
132.9 (C), 132.4 (CH), 130.8 (CH), 129.4 (CH), 127.9
(CH), 123.5 (CH), 95.0 (C), 80.1 (C), 67.1 (CH2), 27.8
(CH2), 16.5 (CH2); m/z (M+1)¼361. HRMS calculated for
C20H16N4O3 360.12224, found 360.1214.
3.5.5. 3-[4-(4-Methoxyphenyl)but-3-ynyloxy)-5-phenyl-
1,2,4-triazine (14). Yield 73%, as a yellow orange solid;
mp 114–116 ꢀC; IR (KBr) cmꢁ1: 3020, 2248, 1325, 1214,
1012; 1H NMR (250 MHz, CDCl3) d 9.43 (s, 1H), 8.16 (dd,
J¼1.2 Hz, J0¼8.1 Hz, 2H), 7.61–7.52 (m, 3H), 7.26 (d, J¼
8.5 Hz, 2H), 6.78 (d, J¼8.5 Hz, 2H), 4.78 (t, J¼7.2 Hz, 2H),
3.79 (s, 3H), 3.02 (t, J¼7.2 Hz, 2H); 13C NMR (62.9 MHz,
CDCl3) d 165.3 (C), 159.4 (C), 158.1 (C), 141.8 (CH),
133.1 (CH), 132.9 (CH), 132.3 (C), 129.5 (CH), 128.0 (CH),
115.6 (C), 113.9 (CH), 83.7 (C), 82.2 (C), 66.7 (CH2), 55.3
(CH3), 20.2 (CH2); m/z (M+1)¼332. HRMS calculated for
C20H16N3O2 (MꢁH)+ 330.12425, found 330.1210.
3.5.10. 3-[5-(4-Methoxyphenyl)-pent-4-ynyloxy]-5-phen-
yl-1,2,4-triazine (19). Yield 70%, as a maroon oil; IR
(KBr) cmꢁ1: 3444, 3068, 2214, 1425, 1213; 1H NMR
(250 MHz, CDCl3) d 9.41 (s, 1H), 8.15 (dd, J¼1.8 Hz,
J0¼8.4 Hz, 2H), 7.60–7.53 (m, 3H), 7.26 (d, J¼8.6 Hz,
2H), 6.77 (d, J¼8.6 Hz, 2H), 4.76 (t, J¼6.2 Hz, 2H), 3.78 (s,
3H), 2.65 (t, J¼6.9 Hz, 2H), 2.26 (tt, J¼6.2 Hz, J0¼6.9 Hz,
2H); 13C NMR (62.9 MHz, CDCl3) d 165.5 (C), 159.2 (C),
157.9 (C), 141.5 (CH), 133.2 (C), 133.0 (CH), 132.8 (CH),
129.4 (CH), 127.9 (CH), 115.9 (C), 113.9 (CH), 87.1 (C),
81.2 (C), 67.5 (CH2), 55.3 (CH3), 28.2 (CH2), 16.3 (CH2);
m/z (M+1)¼346. HRMS calculated for C21H19N3O2
345.14773, found 345.1494.
3.5.6. 5-Phenyl-3-(4-pyrid-4-ylpent-4-ynyloxy)-1,2,4-tri-
azine (15). Yield 74%, as a yellow solid; mp 120–122 ꢀC;
1
IR (KBr) cmꢁ1: 3390, 3025, 2212, 1614, 1012; H NMR
(250 MHz, CDCl3) d 9.43 (s, 1H), 8.51 (d, J¼4.8 Hz, 2H),
8.16 (d, J¼6.9 Hz, 2H), 7.64–7.51 (m, 3H), 7.24 (d, J¼
4.8 Hz, 2H), 4.76 (t, J¼6.0 Hz, 2H), 2.71 (t, J¼7.0 Hz, 2H),
2.29–2.19 (dt, J¼6.0, 7.0 Hz, 2H); 13C NMR (62.9 MHz,
CDCl3) d 165.4 (C), 158.0 (C), 149.5 (CH), 141.6 (CH),
133.1 (CH), 132.8 (C), 129.4 (CH), 128.6 (CH), 128.4 (C),
127.8 (CH), 94.8 (C), 79.2 (C), 67.1 (CH2), 27.7 (CH2),
16.4 (CH2); m/z (M+1)¼317. HRMS calculated for
C19H17N4O (M+H)+ 317.14024, found 317.1405.
3.5.11. 1-(5-Phenyl-1,2,4-triazin-3-yloxy)-4-thien-2-yl-
but-3-yn-2-ol (30). Yield 53%, as a yellow solid; mp 122–
1
124 ꢀC; IR (KBr) cmꢁ1: 3417, 3017, 1681, 1518, 1215; H
NMR (250 MHz, CDCl3) d 9.42 (s, 1H), 8.18–8.14 (dd,
J¼1.7 Hz, J0¼8.2 Hz, 2H), 7.61–7.48 (m, 3H), 7.24–7.19
(m, 2H), 6.91 (dd, J¼3.5 Hz, J0¼5.0 Hz, 1H), 5.13 (t, J¼
5.2 Hz, 1H), 4.82 (d, J¼5.2 Hz, 2H), 3.51 (s, 1H, OH); 13C
NMR (62.9 MHz, CDCl3) d 165.0 (C), 158.0 (C), 141.6
(CH), 132.7 (CH), 132.6 (CH), 129.2 (CH), 127.7 (CH),
127.5 (CH), 126.7 (CH), 121.7 (C), 89.5 (C), 79.6 (C),
71.1 (CH2), 61.5 (CH2); m/z (M+1)¼324. HRMS calculated
for C17H14N3O2S (M+H)+ 324.08067, found 324.0808.
3.5.7. 5-Phenyl-3-(5-thien-2-ylpent-4-ynyloxy)-1,2,4-tri-
azine (16). Yield 97%, as a yellow oil; IR (KBr) cmꢁ1
:
3430, 3022, 2211, 1646, 1542; 1H NMR (250 MHz, CDCl3)
d 9.41 (s, 1H), 8.15 (dd, J¼1.5 Hz, J0¼6.6 Hz, 2H), 7.63–
7.50 (m, 3H), 7.11 (dd, J¼1.0 Hz, J0¼5.1 Hz, 1H), 7.11
(dd, J¼1.0 Hz, J0¼3.8 Hz, 1H), 6.90 (dd, J¼3.8 Hz,
J0¼5.1 Hz, 1H), 4.75 (t, J¼6.4 Hz, 2H), 2.69 (t, J¼7.0 Hz,
2H), 2.17 (tt, J¼6.4 Hz, J0¼7.0 Hz, 2H); 13C NMR
(62.9 MHz, CDCl3) d 165.5 (C), 158.0 (C), 141.6 (CH),
133.2 (C), 132.8 (CH), 131.3 (CH), 129.4 (CH), 127.9 (CH),
126.8 (CH), 126.2 (CH), 123.8 (C), 92.8 (C), 74.6 (C), 67.3
(CH2), 28.2 (CH2), 16.8 (CH2); m/z (M+1)¼322. HRMS
calculated for C18H15N3OS 321.09358, found 321.0928.
3.5.12. 1-(5-Phenyl-1,2,4-triazin-3-yloxy)-4-p-tolylbut-3-
yn-2-ol (31). Yield 49%, as a yellow solid; mp 132–
1
134 ꢀC; IR (KBr) cmꢁ1: 3460, 1670, 1524, 1411, 1278; H
NMR (250 MHz, CDCl3) d 9.44 (s, 1H), 8.16 (dd, J¼
1.2 Hz, J0¼7.8 Hz, 2H), 7.65–7.53 (m, 3H), 7.33 (d,
J¼8.1 Hz, 2H), 7.10 (d, J¼8.1 Hz, 2H), 5.11 (t, J¼5.6 Hz,
1H), 4.84 (t, J¼5.6 Hz, 2H), 2.84 (s, 1H, OH), 2.34 (s, 3H);
13C NMR (62.9 MHz, CDCl3) d 165.3 (C), 158.2 (C), 141.9
(CH), 138.9 (C), 133.0 (CH), 132.9 (C), 131.8 (CH), 129.4
(CH), 129.1 (CH), 128.0 (CH), 119.0 (C), 86.6 (C), 85.2
(C), 71.7 (CH2), 61.7 (CH), 21.5 (CH3); m/z (M+1)¼332.
HRMS calculated for C20H18N3O2 (M+H)+ 332.13990,
found 332.1399.
3.5.8. 5-Phenyl-3-(5-p-tolylpent-4-ynyloxy)-1,2,4-triazine
(17). Yield 76%, as a yellow solid; mp 97–99 ꢀC; IR (KBr)
cmꢁ1: 3425, 3018, 2194, 1620, 1541, 1241; 1H NMR
(250 MHz, CDCl3) d 9.40 (s, 1H), 8.18–8.14 (dd, J¼
1.5 Hz, J0¼8.1 Hz, 2H), 7.59–7.48 (m, 3H), 7.26 (d, J¼
8.3 Hz, 2H), 7.04 (d, J¼8.3 Hz, 2H), 4.76 (t, J¼6.4 Hz,
2H), 2.66 (t, J¼7.0 Hz, 2H), 2.31 (s, 3H), 2.16 (tt, J¼6.4,
7.0 Hz, 2H); 13C NMR (62.9 MHz, CDCl3) d 165.5 (C),
157.9 (C), 141.5 (CH), 137.7 (C), 133.2 (C), 132.7 (CH),
131.5 (CH), 129.4 (CH), 129.0 (CH), 127.9 (CH), 120.6
3.5.13. 4-(4-Methoxyphenyl)-1-(5-phenyl-1,2,4-triazin-3-
yloxy)-but-3-yn-2-ol (32). Yield 55%, as a yellow solid;
mp 120–122 ꢀC; IR (KBr) cmꢁ1: 3244, 3004, 1671, 1509,
1
1471, 1217; H NMR (250 MHz, CDCl3) d 9.45 (s, 1H),

Y. Hajbi et al. / Tetrahedron 63 (2007) 8286–8297
8293
8.16 (dd, J¼1.2 Hz, J0¼7.8 Hz, 2H), 7.62–7.52 (m, 3H),
7.37 (d, J¼6.9 Hz, 2H), 6.81 (d, J¼6.9 Hz, 2H), 5.10 (t,
J¼5.6 Hz, 1H), 4.84 (d, J¼5.6 Hz, 2H), 3.81 (s, 3H), 2.86
(s, 1H, OH); 13C NMR (62.9 MHz, CDCl3) d 165.3 (C),
159.9 (C), 158.2 (C), 141.9 (CH), 133.4 (CH), 133.0 (CH),
133.0 (C), 129.5 (CH), 128.0 (CH), 114.2 (C), 114.0 (CH),
86.5 (C), 84.3 (C), 71.7 (CH2), 61.7 (CH), 55.4 (CH3); m/z
(M+1)¼348. HRMS calculated for C20H17N3O3 347.12699,
found 347.1272.
3.5.18. 1-(4-Nitrophenyl)-5-(5-phenyl-1,2,4-triazin-3-
yloxy)-pent-1-yn-3-ol (37). Yield 64%, as a white solid;
mp 144–146 ꢀC; IR (KBr) cmꢁ1: 3440, 3230, 2235, 1810,
1
1530, 1120; H NMR (250 MHz, CDCl3) d 9.41 (s, 1H),
8.16–8.10 (m, 4H), 7.61–7.52 (m, 5H), 5.04–4.86 (m, 3H),
2.86 (d, J¼5.3 Hz, 1H, OH), 2.49–2.41 (m, 2H); 13C NMR
(62.9 MHz, CDCl3) d 165.4 (C), 158.3 (C), 147.3 (C),
141.8 (CH), 133.1 (C), 132.9 (C), 132.6 (CH), 129.5 (CH),
129.3 (CH), 127.9 (CH), 123.6 (CH), 94.6 (C), 83.5 (C), 64.9
(CH2), 60.0 (CH), 36.8 (CH2); m/z (M+1)¼377. HRMS
calculated for C20H16N4O4 376.11716, found 376.1166.
3.5.14. 4-(4-Nitrophenyl)-1-(5-phenyl-1,2,4-triazin-3-
yloxy)-but-3-yn-2-ol (33). Yield 42%, as a yellow solid;
mp 152–154 ꢀC; IR (KBr) cmꢁ1: 3330, 2270, 1822, 1579,
1518, 1365, 1318, 1087; 1H NMR (250 MHz, CDCl3)
d 9.47 (s, 1H), 8.17 (m, 4H), 7.63–7.54 (m, 5H), 5.18 (t,
J¼5.3 Hz, 1H), 4.88 (d, J¼5.3 Hz, 2H,), 3.28 (s, 1H, OH);
13C NMR (62.9 MHz, CDCl3) d 165.3 (C), 158.5 (C),
147.5 (C), 142.2 (CH), 133.2 (CH), 132.8 (CH), 132.7 (C),
129.6 (CH), 129.0 (C), 128.0 (C), 123.7 (CH), 91.1 (C),
84.6 (C), 71.3 (CH2), 61.8 (CH); m/z (M+1)¼363. HRMS
calculated for C19H14N4O4 362.10151, found 362.0998.
3.6. General procedure for the intramolecular inverse
electron demand Diels–Alder reaction
Triazines 10–19 or 30–37 (0.33 mmol) were dissolved in
chlorobenzene (2 mL) and heated at 180–240 ꢀC under
microwave irradiation (3–6 bars of pressure can be in-
volved). The reaction was monitored by TLC (reaction
time–temperature; see Tables 3, 5 and 6). After complete
conversion of the starting material, the reaction was purified
by chromatography using petroleum ether–ethyl acetate as
eluant to give the desired products 20–29 or 38–44.
3.5.15. 5-(5-Phenyl-1,2,4-triazin-3-yloxy)-1-(thien-2-yl)-
pent-1-yn-3-ol (34). Yield 70%, as a maroon solid; mp 94–
96 ꢀC; IR (KBr) cmꢁ1: 3356, 2968, 2230, 1672, 1541, 1475,
1256; 1H NMR (250 MHz, CDCl3) d 9.41 (s, 1H), 8.14 (d, J¼
6.9 Hz, 2H), 7.60–7.51 (m, 3H), 7.17 (dd, J¼0.9 Hz, J0¼
5.0 Hz, 1H), 7.17 (dd, J¼0.9 Hz, J0¼3.7 Hz, 1H), 6.91 (dd,
J¼3.7 Hz, J0¼5.0 Hz, 1H), 4.99 (t, J¼6.2 Hz, 1H), 4.89 (m,
2H), 2.79 (s, 1H, OH), 2.38 (m, 2H); 13C NMR (62.9 MHz,
CDCl3) d 165.4 (C), 158.1 (C), 141.5 (CH), 133.0 (C), 132.9
(CH), 132.4 (CH), 129.4 (CH), 127.9 (CH), 127.4 (CH),
127.0 (CH), 122.3 (C), 93.3 (C), 78.6 (C), 65.1 (CH2), 60.0
(CH), 36.8 (CH2); m/z (M+1)¼338. HRMS calculated for
C18H16N3O2S (M+H) 338.09632, found 338.0972.
3.6.1. 6-Phenyl-4-pyrid-4-yl-2,3-dihydrofuro[2,3-b]pyri-
dine (20). Compound 20 was obtained as a white solid
(94% yield), mp 180–182 ꢀC, after purification by column
chromatography (petroleum ether–ethyl acetate, 4:1); IR
(KBr) cmꢁ1: 3017, 1612, 1595, 1498, 1210; 1H NMR
(250 MHz, CDCl3) d 8.72 (d, J¼5.6 Hz, 2H), 7.99 (dd,
J¼1.8, 8.1 Hz, 2H), 7.45–7.40 (m, 5H), 7.33 (s, 1H), 4.65
(t, J¼8.4 Hz, 2H), 3.34 (t, J¼8.4 Hz, 2H); 13C NMR
(62.9 MHz, CDCl3) d 169.5 (C), 156.2 (C), 150.5 (CH),
145.8 (C), 144.6 (C), 138.5 (C), 129.1 (CH), 128.7 (CH),
126.8 (CH), 122.3 (CH), 115.8 (C), 112.5 (CH), 69.2 (CH2),
28.1 (CH2); m/z (M+1)¼275. Calcd for C18H14N2O: C,
78.81; H, 5.14; N, 10.21. Found: C, 77.95; H, 5.07; N, 10.02.
3.5.16. 5-(5-Phenyl-1,2,4-triazin-3-yloxy)-1-p-tolylpent-
1-yn-3-ol (35). Yield 81%, as a yellow solid; mp 74–
76 ꢀC; IR (KBr) cmꢁ1: 3400, 3018, 1644, 1542, 1398,
3.6.2. 6-Phenyl-4-thien-2-yl-2,3-dihydrofuro[2,3-b]pyri-
dine (21). Compound 21 was obtained as a dark red oil
(82% yield), after purification by column chromatography
(petroleum ether–ethyl acetate, 4:1); IR (KBr) cmꢁ1: 3090,
1718, 1592, 1413, 1214; 1H NMR (250 MHz, CDCl3)
d 8.00 (dd, J¼2.8 Hz, J0¼6.9 Hz, 2H), 7.52–7.38 (m, 6H),
7.16 (dd, J¼3.8 Hz, J0¼5.3 Hz, 1H), 4.69 (t, J¼8.5 Hz,
2H), 3.46 (t, J¼8.5 Hz, 2H); 13C NMR (62.9 MHz, CDCl3)
d 169.7 (C), 155.5 (C), 140.5 (C), 139.7 (C), 138.8 (C), 128.8
(CH), 128.6 (CH), 128.1 (CH), 127.3 (CH), 126.8 (CH),
126.8 (CH), 113.5 (C), 110.9 (CH), 68.9 (CH2), 29.3 (CH2);
m/z (M+1)¼280. Anal. Calcd for C17H13NOS: C, 73.09; H,
4.69; N, 5.01; S, 11.48. Found: C, 73.56; H, 5.13; N, 4.83; S,
10.66.
1
1214; H NMR (250 MHz, CDCl3) d 9.41 (s, 1H), 8.14 (d,
J¼6.5 Hz, 2H), 7.60–7.51 (m, 3H), 7.28 (d, J¼8.3 Hz,
2H), 7.06 (d, J¼8.3 Hz, 2H), 4.98 (t, J¼6.4 Hz, 1H), 4.89
(t, J¼6.2 Hz, 2H), 2.43 (m, 3H), 2.32 (s, 3H); 13C NMR
(62.9 MHz, CDCl3) d 165.4 (C), 158.1 (C), 141.5 (CH),
138.6 (C), 133.0 (C), 132.8 (CH), 131.6 (CH), 129.4 (CH),
129.0 (CH), 127.9 (CH), 119.4 (C), 88.7 (C), 85.5 (C),
65.2 (CH2), 60.0 (CH), 37.0 (CH2), 21.5 (CH3); m/z
(M+1)¼346. HRMS calculated for C21H19N3O2 345.1477,
found 345.1460.
3.5.17. 1-(4-Methoxyphenyl)-5-(5-phenyl-1,2,4-triazin-3-
yloxy)-pent-1-yn-3-ol (36). Yield 64%, as a yellow-chestnut
oil; IR (KBr) cmꢁ1: 3387, 2947, 2220, 1738, 1609, 1412,
1
1241; H NMR (250 MHz, CDCl3) d 9.38 (s, 1H), 8.10
3.6.3. 6-Phenyl-4-p-tolyl-2,3-dihydrofuro[2,3-b]pyridine
(22). Compound 22 was obtained as a yellow solid (99%
yield), mp 118–120 ꢀC, after purification by column chro-
matography (petroleum ether–ethyl acetate, 4:1); IR (KBr)
cmꢁ1: 3017, 1612, 1599, 1514, 1414, 1213; 1H NMR
(250 MHz, CDCl3) d 8.03 (dd, J¼1.2 Hz, J0¼8.2 Hz, 2H),
7.46–7.37 (m, 3H), 7.34 (d, J¼8.3 Hz, 2H), 7.29 (s, 1H),
7.24 (d, J¼8.3 Hz, 2H), 4.61 (t, J¼8.5 Hz, 2H), 3.33 (t,
J¼8.5 Hz, 2H), 2.41 (s, 3H); 13C NMR (62.9 MHz,
CDCl3) d 169.4 (C), 155.5 (C), 147.4 (C), 139.1 (C), 138.8
(dd, J¼1.2 Hz, J0¼6.9 Hz, 2H), 7.61–7.47 (m, 3H), 7.31 (d,
J¼8.4 Hz, 2H), 6.74 (d, J¼8.4 Hz, 2H), 4.94 (t, J¼5.6 Hz,
1H), 4.85 (t, J¼5.4 Hz, 2H), 3.76 (s, 3H), 3.20 (s, 1H,
OH), 2.42 (m, 2H); 13C NMR (62.9 MHz, CDCl3) d 165.4
(C), 159.7 (C), 158.0 (C), 141.4 (CH), 133.2 (CH), 133.0
(C), 132.8 (CH), 129.3 (CH), 127.8 (CH), 114.5 (C), 113.9
(CH), 88.1 (C), 85.2 (C), 65.2 (CH2), 59.9 (CH), 55.2
(CH3), 37.0 (CH2); m/z (M+1)¼362. HRMS calculated for
C21H19N3O3Na (M+Na)+ 384.13241, found 383.1322.

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Y. Hajbi et al. / Tetrahedron 63 (2007) 8286–8297
(C), 135.3 (C), 129.6 (CH), 128.7 (CH), 128.6 (CH), 127.7
(CH), 126.9 (CH), 115.3 (C), 113.2 (CH), 69.1 (CH2), 28.4
(CH2), 21.3 (CH3); m/z (M+1)¼288. Anal. Calcd for
C20H17NO: C, 83.60; H, 5.96; N, 4.87. Found: C, 83.70;
H, 5.77; N, 4.93.
Anal. Calcd for C18H15NOS: C, 73.69; H, 5.15; N, 4.77; S,
10.93. Found: C, 73.19; H, 4.74; N, 5.33; S, 10.91.
3.6.8. 7-Phenyl-5-p-tolyl-3,4-dihydro-2H-pyrano[2,3-
b]pyridine (27). Compound 27 was obtained as a yellow
oil (84% yield), after purification by column chromato-
graphy (petroleum ether–ethyl acetate, 4:1); IR (KBr)
cmꢁ1: 2936, 1602, 1514, 1311; 1H NMR (250 MHz,
CDCl3) d 8.00 (dd, J¼1.6 Hz, J0¼8.1 Hz, 2H), 7.45–7.32
(m, 3H), 7.30 (s, 1H), 7.28 (d, J¼8.2 Hz, 2H), 7.24 (d,
J¼8.2 Hz, 2H), 4.39 (t, J¼5.0 Hz, 2H), 2.69 (t, J¼6.6 Hz,
2H), 2.42 (s, 3H), 1.91 (m, 2H); 13C NMR (62.9 MHz,
CDCl3) d 161.2 (C), 153.7 (C), 152.6 (C), 138.8 (C), 138.0
(C), 136.1 (C), 129.2 (CH), 128.8 (CH), 128.6 (CH), 128.5
(CH), 126.8 (CH), 115.2 (CH), 113.5 (C), 67.2 (CH2), 24.0
(CH2), 22.2 (CH2), 21.3 (CH3); m/z (M+1)¼302. Anal.
Calcd for C21H19NO: C, 83.69; H, 6.35; N, 4.65. Found:
C, 83.76; H, 6.96; N, 4.64.
3.6.4. 4-(4-Nitrophenyl)-6-phenyl-2,3-dihydrofuro[2,3-
b]pyridine (23). Compound 23 was obtained as a yellow
solid (74% yield), mp 160–162 ꢀC, after purification by col-
umn chromatography (petroleum ether–ethyl acetate, 4:1);
1
IR (KBr) cmꢁ1: 3018, 1596, 1511, 1344, 1220; H NMR
(250 MHz, CDCl3) d 8.33 (d, J¼6.9 Hz, 2H), 8.00 (dd,
J¼1.9 Hz, J0¼8.2 Hz, 2H), 7.70 (d, J¼6.9 Hz, 2H), 7.49–
7.39 (m, 3H), 7.34 (s, 1H), 4.68 (t, J¼8.5 Hz, 2H), 3.34 (t,
J¼8.5 Hz, 2H); 13C NMR (62.9 MHz, CDCl3) d 169.5 (C),
156.4 (C), 147.9 (C), 145.2 (C), 144.8 (C), 138.5 (C), 129.3
(CH), 128.8 (CH), 128.8 (CH), 126.9 (CH), 124.2 (CH),
115.8 (C), 112.8 (CH), 69.2 (CH2), 28.2 (CH2); m/z (M+1)¼
319. HRMS calculated for C19H14N2O3 318.10044, found
318.0994.
3.6.9. 5-(4-Nitrophenyl)-7-phenyl-3,4-dihydro-2H-pyr-
ano[2,3-b]pyridine (28). Compound 28 was obtained as
a yellow solid (67% yield), mp 121–123 ꢀC, after purifica-
tion by column chromatography (petroleum ether–ethyl ace-
tate, 4:1); IR (KBr) cmꢁ1: 3018, 1596, 1344, 1220; 1H NMR
(250 MHz, CDCl3) d 8.32 (d, J¼8.5 Hz, 2H), 8.00 (d,
J¼6.9 Hz, 2H), 7.55 (d, J¼6.9 Hz, 2H), 7.58–7.38 (m,
3H), 7.26 (s, 1H), 4.42 (t, J¼5.3 Hz, 2H), 2.64 (t,
J¼6.3 Hz, 2H), 2.05–1.96 (m, 2H); 13C NMR (62.9 MHz,
CDCl3) d 161.4 (C), 154.4 (C), 150.2 (C), 147.8 (C), 145.7
(C), 138.2 (C), 129.7 (CH), 129.3 (CH), 128.7 (CH), 126.8
(CH), 123.9 (CH), 114.4 (CH), 113.1 (C), 67.3 (CH2), 23.8
(CH2), 21.9 (CH2); m/z (M+1)¼333. HRMS calculated for
C20H17N2O3 (M+H)+ 333.12392, found 333.1244.
3.6.5. 4-(4-Methoxyphenyl)-6-phenyl-2,3-dihydro-
furo[2,3-b]pyridine (24). Compound 24 was obtained as
a white solid (83% yield), mp 136–138 ꢀC, after purification
by column chromatography (petroleum ether–ethyl acetate,
1
4:1); IR (KBr) cmꢁ1: 3032, 1595, 1414, 1228; H NMR
(250 MHz, CDCl3) d 8.03 (dd, J¼1.8, 7.8 Hz, 2H), 7.52–
7.36 (m, 3H), 7.30 (d, J¼6.6 Hz, 2H), 6.96 (d, J¼6.6 Hz,
2H), 4.63 (t, J¼8.4 Hz, 2H), 3.40 (t, J¼8.4 Hz, 2H); 13C
NMR (62.9 MHz, CDCl3) d 169.4 (C), 160.0 (C), 155.4 (C),
147.0 (C), 139.0 (C), 130.5 (C), 129.1 (CH), 128.7 (CH),
128.6 (CH), 126.8 (CH), 115.0 (C), 114.3 (CH), 112.9
(CH), 69.0 (CH2), 55.4 (CH3), 28.4 (CH2); m/z (M+1)¼
304. Anal. Calcd for C20H17NO2: C, 79.19; H, 5.65; N,
4.62. Found: C, 78.88; H, 5.57; N, 4.61.
3.6.10. 5-(4-Methoxyphenyl)-7-phenyl-3,4-dihydro-2H-
pyrano[2,3-b]pyridine (29). Compound 29 was obtained
as an orange solid (79% yield), mp 126–128 ꢀC, after purifi-
cation by column chromatography (petroleum ether–ethyl
acetate, 4:1); IR (KBr) cmꢁ1: 3004, 2401, 1600, 1447,
3.6.6. 7-Phenyl-5-pyrid-4-yl-3,4-dihydro-2H-pyrano[2,3-
b]pyridine (25). Compound 25 was obtained as a yellow
solid (72% yield), mp 170–172 ꢀC, after purification by col-
umn chromatography (petroleum ether–ethyl acetate, 3:2);
1
1315; H NMR (250 MHz, CDCl3) d 8.00 (dd, J¼1.3 Hz,
1
IR (KBr) cmꢁ1: 3056, 2942, 1968, 1678, 1592; H NMR
J0¼7.1 Hz, 2H), 7.45–7.25 (m, 6H), 6.97 (d, J¼8.6 Hz,
2H), 4.39 (t, J¼5.0 Hz, 2H), 3.85 (s, 3H), 2.70 (t,
J¼6.3 Hz, 2H), 1.91 (m, 2H); 13C NMR (62.9 MHz,
CDCl3) d 161.2 (C), 159.6 (C), 153.7 (C), 152.2 (C), 138.8
(C), 131.3 (C), 129.9 (CH), 128.8 (CH), 128.6 (CH), 126.8
(CH), 115.2 (CH), 113.9 (CH), 113.5 (C), 67.2 (CH2), 55.4
(CH3), 24.1 (CH2), 22.2 (CH2); m/z (M+1)¼318. Anal.
Calcd for C21H19NO2: C, 79.47; H, 6.03; N, 4.41. Found:
C, 79.54; H, 5.85; N, 4.44.
(250 MHz, CDCl3) d 8.72 (d, J¼5.6 Hz, 2H), 8.00 (dd,
J¼1.2 Hz, J0¼7.3 Hz, 2H), 7.46–7.34 (m, 4H), 7.30 (d,
J¼5.6 Hz, 2H), 4.41 (t, J¼5.0 Hz, 2H), 2.66 (t, J¼6.3 Hz,
2H), 1.95 (m, 2H); 13C NMR (62.9 MHz, CDCl3) d 161.3
(C), 154.4 (C), 150.2 (CH), 149.7 (C), 146.9 (C), 138.3
(C), 129.2 (CH), 128.7 (CH), 126.8 (CH), 123.4 (CH),
114.2 (CH), 113.0 (C), 67.3 (CH2), 23.7 (CH2), 21.9
(CH2); m/z (M+1)¼289. Anal. Calcd for C19H16N2O: C,
79.14; H, 5.59; N, 9.71. Found: C, 78.60; H, 5.43; N, 9.71.
3.6.11. 6-Phenyl-4-thien-2-yl-2,3-dihydrofuro[2,3-b]pyr-
idin-3-ol (38). Compound 38 was obtained as a dark red
foam (40% yield), after purification by column chromato-
graphy (petroleum ether–ethyl acetate, 4:1); IR (KBr)
3.6.7. 7-Phenyl-5-thien-2-yl-3,4-dihydro-2H-pyrano[2,3-
b]pyridine (26). Compound 26 was obtained as a yellow
oil (72% yield), after purification by column chromato-
graphy (petroleum ether–ethyl acetate, 3:2); IR (KBr)
1
cmꢁ1: 3416, 3033, 1585, 1457, 1317; H NMR (250 MHz,
1
cmꢁ1: 2955, 2886, 1592, 1550, 1371; H NMR (250 MHz,
CDCl3) d 7.82 (d, J¼5.6 Hz, 2H), 7.71 (dd, J¼0.9 Hz,
J0¼3.7 Hz, 1H), 7.34 (dd, J¼0.9 Hz, J0¼5.0 Hz, 1H),
7.44–7.32 (m, 4H), 7.07 (dd, J¼3.7 Hz, J0¼5.0 Hz, 1H),
5.45 (dd, J¼2.2 Hz, J0¼5.6 Hz, 1H), 4.64 (d, J¼5.6 Hz,
2H); 13C NMR (62.9 MHz, CDCl3) d 169.1 (C), 158.2 (C),
142.1 (C), 139.0 (C), 138.1 (C), 129.4 (CH), 129.2 (CH),
128.7 (CH), 128.6 (CH), 128.0 (CH), 127.1 (CH), 114.4
(C), 112.2 (CH), 77.9 (CH2), 70.1 (CH2); m/z (M+1)¼296.
CDCl3) d 8.04 (dd, J¼1.9 Hz, J0¼8.1 Hz, 2H), 7.47–7.37
(m, 6H), 7.14 (dd, J¼1.6, 5.3 Hz, 1H), 4.40 (t, J¼5.3 Hz,
2H), 2.91 (t, J¼6.6 Hz, 2H), 2.07–1.98 (m, 2H); 13C NMR
(62.9 MHz, CDCl3) d 161.6 (C), 154.0 (C), 144.7 (C),
139.9 (C), 138.5 (C), 129.0 (CH), 128.6 (CH), 127.9 (CH),
127.6 (CH), 126.9 (CH), 126.8 (CH), 115.1 (CH), 113.3
(C), 67.1 (CH2), 24.5 (CH2), 22.1 (CH2); m/z (M+1)¼294.

Y. Hajbi et al. / Tetrahedron 63 (2007) 8286–8297
8295
Anal. Calcd for C17H13NO2S: C, 69.13; H, 4.44; N, 4.74; S,
10.86. Found: C, 69.18; H, 4.46; N, 4.69; S, 10.36.
3.6.16. 7-Phenyl-5-p-tolyl-3,4-dihydro-2H-pyrano[2,3-
b]pyridin-4-ol (43). Compound 43 was obtained as a white
solid (39% yield), mp 175–177 ꢀC, after purification by col-
umn chromatography (petroleum ether–ethyl acetate, 3:2);
3.6.12. 6-Phenyl-4-p-tolyl-2,3-dihydrofuro[2,3-b]pyri-
din-3-ol (39). Compound 39 was obtained as a brown
foam (40% yield), after purification by column chromato-
graphy (petroleum ether–ethyl acetate, 3:2); IR (KBr)
1
IR (KBr) cmꢁ1: 3438, 2939, 1592, 1515, 1397; H NMR
(250 MHz, CDCl3) d 8.02 (d, J¼7.5 Hz, 2H), 7.43–7.38
(m, 5H), 7.27 (m, 3H), 4.83 (t, J¼2.5 Hz, 1H), 4.64–4.45
(m, 2H), 2.43 (s, 3H), 2.06–1.99 (m, 2H); 13C NMR
(62.9 MHz, CDCl3) d 160.8 (C), 155.9 (C), 154.1 (C),
138.5 (C), 138.4 (C), 135.3 (C), 129.4 (CH), 129.3 (CH),
128.7 (CH), 128.5 (CH), 127.1 (CH), 115.8 (CH2), 115.0
(C), 62.1 (CH2), 60.5 (CH), 30.1 (CH2), 21.3 (CH3); m/z
(M+1)¼318. HRMS calculated for C21H19NO2 317.14158,
found 317.1423.
1
cmꢁ1: 3444, 3034, 1598, 1435, 1278; H NMR (250 MHz,
CDCl3) d 7.95 (d, J¼7.8 Hz, 2H), 7.61 (d, J¼8.1 Hz, 2H),
7.43–7.34 (m, 4H), 7.25 (d, J¼8.1 Hz, 2H), 5.41 (dd,
J¼3.1 Hz, J0¼4.7 Hz, 1H), 4.58 (d, J¼4.7 Hz, 2H), 2.41
(s, 3H); 13C NMR (62.9 MHz, CDCl3) d 168.9 (C), 158.2
(C), 149.9 (C), 139.3 (C), 138.6 (C), 134.3 (C), 129.8
(CH), 129.3 (CH), 128.7 (CH), 128.3 (CH), 127.2 (CH),
116.5 (C), 114.0 (CH), 77.7 (CH2), 69.9 (CH), 21.4 (CH3);
m/z (M+1)¼304. Anal. Calcd for C20H17NO2: C, 79.19; H,
5.65; N, 4.62. Found: C, 79.52; H, 5.47; N, 4.69.
3.6.17. 5-(4-Methoxyphenyl)-7-phenyl-3,4-dihydro-2H-
pyrano[2,3-b]pyridin-4-ol (44). Compound 44 was ob-
tained as a yellow oil (64% yield), after purification by col-
umn chromatography (petroleum ether–ethyl acetate, 4:1);
3.6.13. 4-(4-Methoxyphenyl)-6-phenyl-2,3-dihydro-
furo[2,3-b]pyridin-3-ol (40). Compound 40 was obtained
as a yellow-orange solid (82% yield), mp 170–172 ꢀC, after
purification by column chromatography (petroleum ether–
ethyl acetate, 4:1); IR (KBr) cmꢁ1: 3444, 3014, 1604,
1514, 1441; 1H NMR (250 MHz, CDCl3) d 7.92 (d,
J¼7.8 Hz, 2H), 7.68 (d, J¼8.9 Hz, 2H), 7.43–7.35 (m,
4H), 6.97 (d, J¼8.9 Hz, 2H), 5.39 (dd, J¼3.1 Hz, J0¼4.8 Hz,
1H), 4.60 (d, J¼4.8 Hz, 2H), 3.86 (s, 3H), 3.08 (s, 1H); 13C
NMR (62.9 MHz, CDCl3) d 169.0 (C), 160.5 (C), 158.1 (C),
149.5 (C), 138.6 (C), 129.8 (CH), 129.6 (C), 129.5 (C), 129.3
(CH), 128.7 (CH), 127.2 (CH), 114.5 (CH), 113.8 (CH), 77.8
(CH2), 70.0 (CH), 55.5 (CH3); m/z (M+1)¼320. Anal. Calcd
for C20H17NO2+H2O (33%): C, 73.83; H, 5.47; N, 4.30.
Found: C, 73.95; H, 5.19; N, 4.41.
1
IR (KBr) cmꢁ1: 3368, 3014, 1604, 1519, 1414; H NMR
(250 MHz, CDCl3) d 8.02 (d, J¼8.1 Hz, 2H), 7.49–7.40
(m, 5H), 7.30 (s, 1H), 6.99 (d, J¼6.5 Hz, 2H), 4.85 (t,
J¼3.1 Hz, 1H), 4.65–3.87 (m, 2H), 3.87 (s, 3H), 2.04–2.01
(m, 2H); 13C NMR (62.9 MHz, CDCl3) d 160.8 (C), 159.9
(C), 156.0 (C), 153.8 (C), 138.4 (C), 130.5 (C), 130.0
(CH), 129.4 (CH), 128.7 (CH), 127.1 (CH), 115.9 (CH),
115.0 (C), 114.1 (CH), 62.1 (CH2), 60.6 (CH), 55.5 (CH3),
30.2 (CH2); m/z (M+1)¼334. HRMS calculated for
C21H19NO3 333.13649, found 333.1351.
3.6.18. 7-Phenyl-5-thien-2-yl-2H-pyrano[2,3-b]pyridine
(45). Compound 45 was obtained as a pale yellow oil
(66% yield), after purification by column chromatography
(petroleum ether–ethyl acetate, 4:1); IR (KBr) cmꢁ1: 1684,
1591, 1441, 1371, 1254; 1H NMR (250 MHz, CDCl3)
d 8.04 (m, 2H), 7.51–7.40 (m, 5H), 7.24 (dd, J¼0.9 Hz,
J0¼4.0 Hz, 1H), 7.17 (dd, J¼0.9 Hz, J0¼5.0 Hz, 1H), 6.80
(dt, J¼1.5 Hz, J0¼3.4 Hz, 1H), 5.90 (dt, J¼3.4 Hz,
J0¼7.2 Hz, 1H), 5.15 (dd, J¼1.5 Hz, J0¼7.2 Hz, 2H); 13C
NMR (62.9 MHz, CDCl3) d 161.6 (C), 154.8 (C), 140.6
(C), 139.1 (C), 138.3 (C), 129.2 (CH), 128.7 (CH), 128.5
(CH), 127.9 (CH), 127.4 (CH), 126.8 (CH), 122.8 (CH),
122.2 (CH), 115.6 (CH), 112.8 (C), 66.6 (CH2); m/z
(M+1)¼292.
3.6.14. 4-(4-Nitrophenyl)-6-phenyl-2,3-dihydrofuro[2,3-
b]pyridin-3-ol (41). Compound 41 was obtained as a brown
oil (34% yield), after purification by column chromato-
graphy (petroleum ether–ethyl acetate, 4:1); IR (KBr) cmꢁ1
:
1
3444, 3230, 2170, 1820, 1590, 1335; H NMR (250 MHz,
CDCl3) d 8.33 (dd, J¼1.6 Hz, J0¼8.5 Hz, 2H), 7.98–7.88
(m, 4H), 7.44–7.41 (m, 3H), 7.36 (s, 1H), 5.35 (dd, J¼
3.1 Hz, J0¼4.7 Hz, 1H), 4.67 (d, J¼4.7 Hz, 2H); 13C NMR
(62.9 MHz, CDCl3) d 166.9 (C), 156.9 (C), 145.5 (C),
141.4 (C), 135.8 (C), 135.8 (C), 127.7 (CH), 127.4 (CH),
126.7 (CH), 125.1 (CH), 122.0 (CH), 114.7 (C), 111.7
(CH), 75.2 (CH2), 67.6 (CH); m/z (M+1)¼335. HRMS cal-
culated for C19H14N2O4 334.09536, found 334.0937.
3.6.19. 7-Phenyl-5-p-tolyl-2H-pyrano[2,3-b]pyridine
(46). Compound 46 was obtained as a maroon oil (51%
yield), after purification by column chromatography (petro-
leum ether–ethyl acetate, 4:1); IR (KBr) cmꢁ1: 1577, 1431,
3.6.15. 7-Phenyl-5-thien-2-yl-3,4-dihydro-2H-pyr-
ano[2,3-b]pyridin-4-ol (42). Compound 42 was obtained
as a white solid (40% yield), mp 187–189 ꢀC, after purifica-
tion by column chromatography (petroleum ether–ethyl ace-
tate, 3:2); IR (KBr) cmꢁ1: 3390, 3034, 1684, 1471, 1241; 1H
NMR (250 MHz, CDCl3) d 8.04 (m, 2H), 7.60 (dd,
J¼1.2 Hz, J0¼3.7 Hz, 1H), 7.58–7.41 (m, 5H), 7.15 (dd,
J¼3.7 Hz, J0¼5.3 Hz, 1H), 4.97–4.92 (m, 1H), 4.68–4.49
(m, 2H), 2.31 (s, 1H, OH), 2.10–2.03 (m, 2H); 13C NMR
(62.9 MHz, CDCl3) d 161.1 (C), 156.4 (C), 146.2 (C),
138.7 (C), 138.1 (C), 129.5 (CH), 128.9 (CH), 128.7 (CH),
128.1 (CH), 127.5 (CH), 127.1 (CH), 115.7 (CH), 114.0
(C), 62.0 (CH2), 60.7 (CH), 30.2 (CH2); m/z (M+1)¼310.
HRMS calculated for C18H15NO2S 309.08235, found
309.0808.
1
1100, 908, 733; H NMR (250 MHz, CDCl3) d 7.95 (d,
J¼8.1 Hz, 2H), 7.39–7.32 (m, 3H), 7.31–7.18 (m, 5H),
6.45–6.40 (dt, J¼1.8 Hz, J0¼9.6 Hz, 1H), 5.74–5.67 (dt,
J¼3.4 Hz, J0¼9.6 Hz, 1H), 5.03 (dd, J¼1.8 Hz, J0¼3.4 Hz,
2H), 2.36 (s, 3H); 13C NMR (62.9 MHz, CDCl3) d 161.3
(C), 154.5 (C), 148.4 (C), 138.5 (C), 138.5 (C), 134.8 (C),
129.4 (CH), 129.1 (CH), 129.1 (CH), 128.7 (CH), 126.3
(CH), 126.0 (CH), 122.2 (CH), 115.7 (CH), 112.9 (C),
66.8 (CH2), 21.4 (CH3); m/z (M+1)¼300.
3.6.20. 5-(4-Methoxyphenyl)-7-phenyl-2H-pyrano[2,3-
b]pyridine (47). Compound 47 was obtained as a yellow
oil (14% yield), after purification by column chromato-
graphy (petroleum ether–ethyl acetate, 4:1); IR (KBr)

8296
Y. Hajbi et al. / Tetrahedron 63 (2007) 8286–8297
cmꢁ1: 3014, 1628, 1500, 1452, 1280, 1247, 1038, 757; H
NMR (250 MHz, CDCl3) d 8.04 (dd, J¼1.6 Hz, J0¼8.2 Hz,
2H), 7.46–7.25 (m, 6H), 6.99 (d, J¼6.9 Hz, 2H), 6.50 (dt,
J¼1.9 Hz, J0¼9.8 Hz, 1H), 5.79 (dt, J¼3.4 Hz, J0¼9.8 Hz,
1H), 5.11 (dd, J¼1.9 Hz, J0¼3.4 Hz, 2H), 3.87 (s, 3H); 13C
NMR (62.9 MHz, CDCl3) d 161.4 (C), 160.0 (C), 154.5
(C), 148.1 (C), 138.6 (C), 130.5 (CH), 130.0 (C), 129.1
(CH), 128.7 (CH), 126.8 (CH), 122.3 (CH), 122.1 (CH),
115.6 (CH), 114.1 (CH), 112.9 (C), 66.7 (CH2), 55.5
(CH3); m/z (M+1)¼316.
1
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