Tandem palladium/charcoal-copper(I) iodide (Pd/C-CuI) catalyzed Sonogashira coupling and intramolecular cyclization from 2-bromonicotinic acid (=2-bromopyridine-3-carboxylic acid) and ethynylarenes to 4-azaphthalides (=furo[3,4-b]pyridin-5(7H)-ones) and 5-azaisocoumarins (=5H-pyrano[4,3-b] pyridin-5-ones)

Article abstract of DOI:10.1002/hlca.201100060

Several 4-azaphthalides (=furo[3,4-b]pyridin-5(7H)-ones) and 5-azaisocoumarins (=5H-pyrano[4,3-b]pyridin-5-ones) were prepared through a tandem heterogeneous Pd/C-mediated Sonogashira coupling and a 5-exo-dig or 6-endo-dig intramolecular cyclization of 2-bromonicotinic acid (=2-bromopyridine-3-carboxyclic acid) with various ethynylarenes or 3-ethynylthiophene. In the presence of Pd/C-Ph₃P-CuI and Et ₃N in dry dioxane under Ar at 90°, a mixture of 4-azaphthalides (usually the major product) and 5-azaisocoumarins was obtained after 3.5 h under normal heating (Schemes 3 and 4; Tables 1 and 2). This mixture of compounds was also obtained with the same catalytic system under microwave (MW) irradiation in only 25 min (Tables 3 and 4). The 1-ethynyl-3-methoxybenzene gave on heating only the corresponding 4-azaphthalide (Table 2), while under MW irradiation, both the 5-exo-dig and the 6-endo-dig products were obtained (Table 4). For the 3-ethynylthiophene, the regioselectivity for the corresponding 4-azaphthalide was achieved with both methods (Tables 2 and 4). Although the yields and the regioselectivity of the reaction generally remained the same with both methods, the use of MW allowed us to obtain the corresponding products in a shorter reaction time. From 4-ethynyl-N,N-dimethylaniline (=4-ethynyl-N,N- dimethylbenzenamine), the corresponding 4-azaphthalide and 5-isocoumarin were only obtained under MW irradiation (Tables 2 and 4). To the best of our knowledge, it is the first time that this kind of tandem reaction was applied to a pyridine derivative giving the corresponding 4-azaphthalides and 5-azaisocoumarins which are easily separated and may both show biological activity. Copyright

Full text of DOI:10.1002/hlca.201100060

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Helvetica Chimica Acta – Vol. 94 (2011)
Tandem Palladium/Charcoal-Copper(I) Iodide (Pd/C-CuI) Catalyzed
Sonogashira Coupling and Intramolecular Cyclization from 2-Bromonicotinic
Acid (¼2-Bromopyridine-3-carboxylic Acid) and Ethynylarenes to 4-
Azaphthalides (¼ Furo[3,4-b]pyridin-5(7H)-ones) and 5-Azaisocoumarins
(¼ 5H-Pyrano[4,3-b]pyridin-5-ones)
by Agathe Begouin and Maria-Joa˜o R. P. Queiroz*
Centro de Quꢀmica, Universidade do Minho, Campus de Gualtar, PT-4710-057 Braga
(phone: þ 351-253-604378/70; fax: þ 351-253-604382; e-mail: mjrpq@quimica.uminho.pt)
Several 4-azaphthalides (¼ furo[3,4-b]pyridin-5(7H)-ones) and 5-azaisocoumarins (¼ 5H-pyra-
no[4,3-b]pyridin-5-ones) were prepared through a tandem heterogeneous Pd/C-mediated Sonogashira
coupling and a 5-exo-dig or 6-endo-dig intramolecular cyclization of 2-bromonicotinic acid (¼2-
bromopyridine-3-carboxyclic acid) with various ethynylarenes or 3-ethynylthiophene. In the presence of
Pd/CꢀPh3PꢀCuI and Et3N in dry dioxane under Ar at 908, a mixture of 4-azaphthalides (usually the
major product) and 5-azaisocoumarins was obtained after 3.5 h under normal heating (Schemes 3 and 4;
Tables 1 and 2). This mixture of compounds was also obtained with the same catalytic system under
microwave (MW) irradiation in only 25 min (Tables 3 and 4). The 1-ethynyl-3-methoxybenzene gave on
heating only the corresponding 4-azaphthalide (Table 2), while under MW irradiation, both the 5-exo-dig
and the 6-endo-dig products were obtained (Table 4). For the 3-ethynylthiophene, the regioselectivity for
the corresponding 4-azaphthalide was achieved with both methods (Tables 2 and 4). Although the yields
and the regioselectivity of the reaction generally remained the same with both methods, the use of MW
allowed us to obtain the corresponding products in a shorter reaction time. From 4-ethynyl-N,N-
dimethylaniline (¼4-ethynyl-N,N-dimethylbenzenamine), the corresponding 4-azaphthalide and 5-
isocoumarin were only obtained under MW irradiation (Tables 2 and 4). To the best of our knowledge, it
is the first time that this kind of tandem reaction was applied to a pyridine derivative giving the
corresponding 4-azaphthalides and 5-azaisocoumarins which are easily separated and may both show
biological activity.
Introduction. – Phthalides (¼ isobenzofuran-1(3H)-ones) [1] and isocoumarins
(¼1H-2-benzopyran-1-ones) [2] are important classes of O-containing heterocycles
often seen in naturally occurring and biologically active compounds. One of the most
attractive routes for the synthesis of these compounds is the use of 2-halogenobenzoic
acids and terminal alkynes as starting materials. Usually, this process was performed in
a one-pot two-step reaction: a Sonogashira coupling [3] of 2-iodobenzoic acid with
terminal alkynes followed by an intramolecular cyclization of the 2-alkynylbenzoic
acid, which often results in a mixture of a (3Z)-3-alkylidenephthalide, and a 3-alkyl- or
3-arylisocoumarin via 5-exo-dig and 6-endo-dig cyclizations, respectively (Scheme 1)
[4]. Kundu and co-workers described this heteroannulation process as stereospecific
for the phthalide, since only the (3Z)-isomers of the 3-alkylidenephthalides were
obtained [4a].
ꢁ 2011 Verlag Helvetica Chimica Acta AG, Zꢂrich

Helvetica Chimica Acta – Vol. 94 (2011)
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Scheme 1
Up to now, some o-halogenoheteroarenecarboxylic acids have already been used as
starting materials in this reaction, including 3-iodothiophene-2-carboxylic acid, 2-
bromothiophene-3-carboxylic acid [5], and 3-bromobenzo[b]thiophene-2-carboxylic
acid or the corresponding methyl esters [6]. To the best of our knowledge, the use of
halogenopyridine derivatives has not been fully explored in this process: only three
examples of the synthesis of 7-aryl-5H-pyrano[4,3-b]pyridin-5-one, resulting from a
copper- or gold-catalyzed/Lewis acid mediated 6-endo-dig intramolecular cyclization
under microwave (MW) irradiation of the corresponding methyl or ethyl 2-(2-
arylethynyl)nicotinates (¼ methyl or ethyl 2-(2-arylethynyl)pyridine-3-carboxylic
acids), have already been described by Bihel and co-workers [7] (Scheme 2). However,
in this reaction, they have synthesized and isolated the Sonogashira product separately.
Scheme 2
Recently, the use of 10% Pd/CꢀPh3PꢀCuI has been reported as an efficient
catalytic system for the one-pot coupling/cyclization process from 2-iodobenzoic acids
and terminal alkynes [4d]. Because of the easy recovery of Pd along with the reduced
burden of metal contamination to the products, the use of Pd/C as heterogeneous
catalyst is known to be advantageous compared to other Pd-catalysts or -salts.
Herein, we report for the first time the synthesis of 4-azaphthalides (¼ furo[3,4-
b]pyridin-5(7H)-ones) and 5-azaisocoumarins (¼ 5H-pyrano[4,3-b]pyridin-5-ones) in a
tandem Sonogashira coupling/intramolecular cyclization from 2-bromonicotinic acid
(¼2-bromopyridine-3-carboxylic acid) and ethynylarenes or 3-ethynylthiophene in the
presence of Pd/CꢀPh3PꢀCuI and of Et3N as the base. The reactions were performed
under either normal heating or under MW irradiation.
Results and Discussion. – Optimization experiments were carried out on the
reaction of 2-bromonicotinic acid with ethynylbenzene in the presence of a Pd species
as the catalyst with the ligand Ph3P, CuI as a co-catalyst, and Et3N as the base, and by
changing some parameters (Scheme 3, Table 1). In all the reactions, an excess of

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Scheme 3
Table 1. Effect of Conditions on the One-pot Pd-catalyzed Reaction of 2-Bromonicotinic Acid with
Ethynylbenzene
Entry
Catalytic system
Solvent
Temperature (time)a)
Products (yield [%])
1
2
3
10% Pd/CꢀPh3PꢀCuI
10% Pd/CꢀPh3PꢀCuI
[PdCl2(Ph3P)2]ꢀCuI
dioxane
EtOH
dioxane
358 (1.5 h) and 908 (2 h)
358 (1.5 h) and 708 (2 h)
358 (1.5 h) and 908 (2 h)
1a (41) þ 1b (27)
1a (n.o.b)) þ 1b (20)
1a (32) þ 1b (35)
a) See General Procedure in the Exper. Part. b) Not observed.
ethynylbenzene (1.5 equiv.) was used, as it is well known that an important side
reaction, namely the Glaser-type oxidative dimerization of the alkyne moiety, usually
occurs in the presence of CuI [8].
Recently, Pal has shown that during the optimization of the reaction conditions for
the Pd/C-mediated synthesis of an isocoumarin, the corresponding phthalide was
isolated as the major product when 1,4-dioxane was used as solvent [9]. Thus, with the
Pd/CꢀPh3PꢀCuI system and Et3N in 1,4-dioxane (Table 1, Entry 1), the 4-azaphthalide
(7Z)-7-benzylidenefuro[3,4-b]pyridin-5(7H)-one (1a) was obtained as the major
product and the 5-azaisocoumarin 7-phenyl-5H-pyrano[4,3-b]pyridin-5-one (1b) [7]
as the minor product, via a 5-exo-dig and a 6-endo-dig cyclization of the Sonogashira
intermediate, respectively. No reaction was observed in DMF or toluene.
We tried to increase the regioselectivity of the reaction with the intention to get
only one product. It has been observed by Pal and co-workers that the 2-iodobenzoic
acid reacts smoothly with terminal alkynes in the presence of Pd/CꢀPh3PꢀCuI as the
catalytic system and Et3N in EtOH to give in good yields only the corresponding
isocoumarins [4d]. In our case, with EtOH as solvent, 5-azaisocoumarin 1b was indeed
the only expected product but in a low yield (Table 1, Entry 2), besides a considerable
amount of the alkyne dimer. We then changed the catalytic system to [PdCl2(Ph3P)2],
which had been shown to exhibit greater selectivity for phthalides [4a,b]. In our system,
in the presence of this catalyst, both 4-azaphthalide 1a and 5-azaisocoumarin 1b were
isolated in almost equal amounts (Table 1, Entry 3). Stirring for a longer time
(overnight) at 908 (or 708 with EtOH) had no effect on the product yields.
Finally, the conditions described in Table 1, Entry 1 seemed to be the best even in
view of the formation of both products. Having these results in hands, several reactions
were performed with different ethynylarenes or 3-ethynylthiophene in the presence of
Pd/CꢀPh3PꢀCuI and Et3N as the base in dry dioxane (Scheme 4). The results of these
experiments are listed in Table 2.

Helvetica Chimica Acta – Vol. 94 (2011)
1795
Scheme 4
Table 2. Synthesis of 4-Azaphthalides (a) and 5-Azaisocoumarins (b) from 2-Bromonicotinic Acid and
Ethynylarenesa)
Entry
(Het)Ar of (Het)ArꢀCꢁCH
Products (yield [%])
4-Azaphthalides
5-Azaisocoumarins
1
2
3
4
5
6
7
8
3-MeOꢀC6H4
4-MeOꢀC6H4
2-MeOꢀC6H4
3-FꢀC6H4
2a (55)
3a (44)
4a (25)
5a (40)
6a (40)
7a (45)
8a (n.o.)b)
9a (50)
2b (n.o.)b)
3b (26)
4b (40)
5b (21)
6b (16)
4-FꢀC6H4
2-FꢀC6H4
7b (18)
4-Me2NꢀC6H4
thiophen-3-yl
8b (n.o.)b)
9b (n.o.)
a) Conditions: 2-bromonicotinic acid (1 equiv.), ArCꢁCH (1.5 equiv.), 10% Pd/C (3 mol-%), Ph3P
(12 mol-% ), CuI (6 mol-%), Et3N (5 equiv.), and dry dioxane; 1.5 h at 358 and 2 h at 908, under Ar (see
General Procedure in the Exper. Part.). b) Only formed and isolated when the reaction was performed
under MW irradiation (Table 4).
From 1-ethynyl-3-methoxybenzene (Table 2, Entry 1), 4-azaphthalide 2a was
formed in good yield (55%), and only traces of the corresponding 5-azaisocoumarin
2b were obtained. With 1-ethynyl-4-methoxybenzene, 4-azaphthalide 3a was the major
product (44%), but 5-azaisocoumarin 3b [7] was also isolated in 26% yield (Table 2,
Entry 2). These two results corroborate the observation made by Kanazawa and
Terada [10] for the organic base-catalyzed intramolecular cyclization, according to
which the presence of electron-donating groups at the phenyl ring of the Sonogashira
products diminish the electrophilic nature at the b-position of the triple bond, thus
favoring the formation of the 5-exo-dig cyclized products. In our case, the 5-exo-dig
cyclization of the carboxylate to the triple bond (! product of type a) may also be
assisted by the conjugate acid of Et3N (Scheme 5).
In contrast to these previous results, with 1-ethynyl-2-methoxybenzene, the 4-
azaphthalide 4a was isolated in 25% yield only, and the corresponding 5-azaisocou-
marin 4b was the major product (40%) (Table 2, Entry 3). In fact, Kanazawa and
Terada have also observed that the presence of a 2-MeO group at the arenyl moiety
substituting the alkyne could diminish the yield of the phthalide [10] (though in their
case, it still remains the major product).
The influence of the position of the substituent was not observed when different
ethynylfluorobenzenes were used as starting materials (Table 2, Entries 4 – 6). In these
cases, the expected 4-azaphthalides 5a – 7a were always formed as the major products

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Helvetica Chimica Acta – Vol. 94 (2011)
Scheme 5
(40 – 45%), and the 5-azaisocoumarins 5b – 7b were the minor products (16 – 21%).
Finally, a reaction involving the electron-rich 4-ethynyl-N,N-dimethylaniline (¼4-
ethynyl-N,N-dimethylbenzenamine) was also tried, but only traces of the expected
products 8a and 8b were observed by 1H-NMR measurements (Table 2, Entry 7). With
the electron-rich 3-ethynylthiophene, the 4-azaphthalide 9a was obtained regioselec-
tively in 50% yield (Table 2, Entry 8), whereas with the electron-deficient 3-
ethynylpyridine, neither the corresponding 4-azaphthalide nor the 5-azaisocoumarin
was formed, but only the dimer of the alkyne was produced.
The same reactions described in Schemes 3 and 4 were performed under microwave
irradiation. The reaction of ethynylbenzene as starting material was first studied to
determine the most effective conditions (Table 3). The 4-azaphthalide 1a and the 5-
azaisocoumarin 1b (cf. Scheme 3 and Table 1) were obtained after MW irradiation of
the solution at 358 for 7.5 min and then at 908 for 10 min (Table 3, Entry 1). Doubling
the time of irradiation at 358 (Table 3, Entry 2) allowed the formation of these
compounds in higher yields (40% of 1a and 18% of 1b), similar to those obtained
under normal heating (41 and 27%, resp.; Table 1, Entry 1). On the other hand, when
the reaction mixture was irradiated at 908 immediately after the addition of the
ethynylbenzene, only the alkyne dimer was obtained (Table 3, Entry 3).
Table 3. Determination of the Most Efficient Reaction Temperature and Time under MW and the
Conditions Described in Table 2
Entry
Solvent
Temperature (time)
Results [%]
1
2
3
dioxane
dioxane
dioxane
358 (7.5 min) and 908 (10 min)
358 (15 min) and 908 (10 min)
908 (20 min)
1a(28) þ 1b (6)
1a (40) þ 1b (18)
n.o.a)
a) Only the ethynylbenzene dimer was formed.
It was then decided to use the conditions defined in Table 3, Entry 2, to perform the
reactions under MW with the other terminal alkynes. Under these conditions, most of
the corresponding 4-azaphthalides and 5-azaisocoumarins (Table 4, Entries 2 – 5) were
obtained in comparable yields to those obtained by conventional heating (cf. Table 2).
With 1-ethynyl-3-methoxybenzene (Table 4, Entry 1), the 4-azaphthalide 2a was
obtained in 45% yield, which is lower than the yield obtained under classical heating
(55%; Table 2, Entry 1), together with the 5-azaisocoumarin 2b in 16% yield, which was

Helvetica Chimica Acta – Vol. 94 (2011)
1797
not isolated previously (Table 2, Entry 1). Under MW irradiation, we were also able to
isolate products 8a and 8b resulting from the reaction of 2-bromonicotinic acid with 4-
ethynyl-N,N-dimethylaniline (Table 4, Entry 6), which were not formed by classical
heating (Table 2, Entry 7). The reaction with 3-ethynylthiophene (Table 4, Entry 7)
afforded the 4-azaphthalide 9a in a good yield (52%) and, as previously observed, the
corresponding 5-azaisocoumarin was not formed. We also tried to perform a reaction
with 3-ethynylpyridine, but as it has already been observed by heating, only the dimer
of the alkyne was obtained.
Table 4. Results and Yields of the Synthesis of 4-Azaphthalides and 5-Azaisocoumarins Performed under
Microwave Irradiation (Conditions of Table 3, Entry 2)
Entry
(Het)Ar of (Het)ArꢀCꢁCH
Products (yield [%])
4-Azaphthalides
5-Azaisocoumarins
1
2
3
4
5
6
7
3-MeOꢀC6H4
4-MeOꢀC6H4
2-MeOꢀC6H4
3-FꢀC6H4
2a (45)
3a (43)
4a (21)
5a (38)
7a (45)
8a (24)
9a (52)
2b (16)
3b (23)
4b (41)
5b (18)
7b (11)
8b (16)
n.o.a)
2-FꢀC6H4
4-Me2NꢀC6H4
thiophen-3-yl
a) Not observed.
Conclusions. – We described for the first time the synthesis of 4-azaphthalides and
5-azaisocoumarins from 2-bromonicotinic acid and terminal alkynes by a tandem Pd/
CꢀCuIꢀPh3PꢀNEt3 mediated reaction of Sonogashira/5-exo-dig or 6-endo-dig intra-
molecular cyclization, performed under either classical heating or MW irradiation. The
corresponding 4-azaphthalides and 5-azaisocoumarins were obtained and readily
separated. The 4-azaphthalides were usually the major products, and from 1-ethynyl-3-
methoxybenzene, it was the only product isolated after heating, but both compounds
were found after MW irradiation. The regioselectivity for the corresponding 4-
azaphthalide was only achieved when 3-ethynylthiophene was used as starting material,
and this with both procedures. From 4-ethynyl-N,N-dimethylaniline, the corresponding
4-azaphthalide and 5-azaisocoumarin were only obtained under MW irradiation. Both
the 4-azaphthalides and 5-azaisocoumarins obtained in this work may present
interesting biological activities.
This work has been supported by the Foundation for Science and Technology (FCT) – Portugal and
FEDER (Fundo Europeu de Desenvolvimento Regional) through the Centro de Quꢀmica/UM, through
the Portuguese NMR network (Bruker 400) and through the post-doctoral grant attributed to A. B.
(SFRH/BPD/36753/2007).
Experimental Part
General. The reactions were monitored by TLC and carried out either under conventional heating in
Schlenk tubes dried under vacuum with a heat gun, or under microwave irradiation in an appropriate
tube at constant temp., in a microwave-accelerated reaction system, model MARSꢃ (version 194A04,

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Helvetica Chimica Acta – Vol. 94 (2011)
Copyright 1997, 2006 by CEM Corporation). The temp. was measured and controlled by a built-in IR
detector. Column chromatography (CC): Macherey-Nagel silica gel (SiO2; 230 – 400 mesh); solvent
gradient from neat petroleum ether (40 – 608) to Et2O/petroleum ether (40 – 608), in steps of 10% of Et2O
each time until the isolation of the products; monitoring by TLC. M.p.: Stuart SMP3; uncorrected. IR
Spectra: Bomem FTLA-2000-104, nujol mulls unless stated otherwise, in cmꢀ1 1H- and 13C-NMR
.
Spectra: Varian Unity Plus at 300 and 75.4 MHz, resp., or Bruker Avance III at 400 and 100.6 MHz, resp;
2D 1H/13C correlations for the assignment of some signals (HMSC, HMBC). EI- and HR-MS: recorded
by the mass spectrometry service of the University of Vigo, Spain; in m/z (rel. %).
General Procedure. Conditions A: In a dry Schlenk tube, 2-bromonicotinic acid, 10% Pd/C (3 mol-
%), Ph3P (12 mol-%), CuI (6 mol-%), and Et3N (5 equiv.) were successively added under Ar to dry
dioxane (2.5 ml per 0.5 mmol of 2-bromonicotinic acid), and the resulting soln. was stirred for 30 min at
358. Then, ethynylarene was added, and the mixture was stirred for 1 h at 358 and then for 2 h at 908.
Conditions B: The 2-bromonicotinic acid, 10% Pd/C (3 mol-%), Ph3P (12 mol-%), CuI (6 mol-%), and
Et3N (5 equiv.) were added under Ar in an appropriate tube containing dry dioxane (2.5 ml per 0.5 mmol
of 2-bromonicotinic acid), and the resulting soln. was irradiated under microwave (power max. 400 W)
at 358 for 5 min. Then, the ethynylarene was added, and the mixture was irradiated at 358 for 10 min
(power max. 800 W) and at 908 for 10 min (power max. 1600 W). General Workup for Both Procedures:
After cooling, CHCl3 was added, the mixture was transferred to a round-bottom flask, and the solvents
were evaporated. The resulting oil was submitted to CC (SiO2) to give the corresponding products as
solids.
(7Z)-7-(Phenylmethylidene)furo[3,4-b]pyridin-5(7H)-one (1a) and 7-Phenyl-5H-pyrano[4,3-b]pyr-
idin-5-one (1b). From 2-bromonicotinic acid (101 mg, 0.500 mmol) and ethynylbenzene (78.0 mg,
0.750 mmol). CC (40% Et2O/petroleum ether): 1a (A: 46.0 mg, 41%; B: 45.0 mg, 40%) as a yellow solid.
Recrystallization from Et2O/petroleum ether gave yellow crystals. M.p. 145 – 1478. IR: 1776 (C¼O).
1H-NMR (400 MHz, CDCl3): 6.96 (s, PhCH¼C); 7.35 – 7.38 (m, 1 arom. H); 7.42 – 7.48 (m, 3 arom. H);
7.89 – 7.91 (m, 2 arom. H); 8.24 (dd, J ¼ 7.6, 1.6, HꢀC(4)); 8.92 (d, J ¼ 4.8, 1.6, HꢀC(2)). 13C-NMR
(100.6 MHz, CDCl3): 108.73 (PhCH¼C); 117.33 (C); 124.08 (C(3)); 128.83 (2 CH); 129.14 (CH); 130.74
(2 CH); 132.48 (C); 133.71 (C(4)); 143.69 (C(7)); 156.18 (C(2)); 158.53 (C); 164.78 (C¼O). EI-MS:
224.07 (6, [M þ 1]þ), 223.06 (46, Mþ), 222.06 (100, [M ꢀ 1]þ), 167.07 (18), 166.06 (27). HR-MS: 223.0631
(Mþ, C14H9NOþ2 ; calc. 223.0633).
Compound 1b was isolated from CC (60% Et2O/petroleum ether): yellow solid (A: 30.0 mg, 27%; B:
20.0 mg, 18%). Recrystallization from Et2O/petroleum ether gave yellow crystals. M.p. 135 – 1368 ([7]:
136 – 1378). Spectroscopic data: already reported in the lit. similar to the ones obtained in this work.
(7Z)-7-[(3-Methoxyphenyl)methylidene]furo[3,4-b]pyridin-5(7H)-one (2a) and 7-(3-Methoxyphen-
yl)-5H-pyrano[4,3-b]pyridin-5-one (2b). From 2-bromonicotinic acid (101 mg, 0.500 mmol) and 1-
ethynyl-3-methoxybenzene (99.0 mg, 0.750 mmol). CC (40% Et2O/petroleum ether): 2a (A: 70.0 mg,
55%; B: 57.0 mg, 45%) as a beige solid. Recrystallization from Et2O/petroleum ether gave yellow crystals.
M.p. 152 – 1538. IR: 1781 (C¼O). 1H-NMR (400 MHz, CDCl3): 3.90 (s, MeO); 6.92 – 6.95 (m, 2 arom. H,
ArCH¼C); 7.33 – 7.38 (m, 1 arom. H); 7.46 – 7.50 (m, 3 arom. H); 8.24 (dd, J ¼ 8.0, 1.6, HꢀC(4)); 8.92 (dd,
J ¼ 4.8, 1.6, HꢀC(2)). 13C-NMR (100.6 MHz, CDCl3): 55.33 (MeO); 108.72 (ArCH¼C); 115.32 (CH);
115.52 (CH); 117.40 (C); 123.50 (CH); 124.14 (C(3)); 129.77 (CH); 133.70 (C); 133.78 (C(4)); 143.80
(C(7)); 156.15 (C(2)); 158.50 (C); 159.80 (MeOꢀC); 164.68 (C¼O). EI-MS: 254.08 (9, [M þ 1]þ), 253.07
(60, Mþ), 252.07 (100, [M ꢀ 1]þ), 238.05 (6, [M ꢀ 15]þ). HR-MS: 253.0739 (Mþ, C15H11NOþ3 ; calc.
253.0739).
Compound 2b was only isolated under MW irradiation (Conditions B: 20.0 mg, 16%) after CC (60%
Et2O/petroleum ether) as a yellow pale solid. Recristallization from Et2O/petroleum ether gave off-white
crystals. M.p. 178 – 1808. IR: 1731 (C¼O). 1H-NMR (400 MHz, CDCl3): 3.90 (s, MeO); 7.02 – 7.50 (m, 1
arom. H); 7.23 (s, HꢀC(8)); 7.39 – 7.46 (m, 3 arom. H); 7.50 – 7.53 (m, 1 arom. H); 8.56 (dd, J ¼ 8.0, 1.6,
HꢀC(4)); 8.95 (dd, J ¼ 4.8, 1.6, HꢀC(2)). 13C-NMR (100.6 MHz, CDCl3): 55.48 (MeO); 103.96 (C(8));
110.70 (CH); 116.91 (CH); 116.99 (C); 118.11 (CH); 122.89 (C(3)); 130.04 (CH); 132.69 (C); 137.59
(C(4)); 155.01 (C); 156.38 (2 CH); 157.14 (C(7)); 160.06 (MeOꢀC); 161.98 (C¼O). EI-MS: 254.08 (15,
[M þ 1]þ), 253.07 (100, Mþ). HR-MS: 253.0738 (Mþ, C15H11NOþ3 ; calc. 253.0739).

Helvetica Chimica Acta – Vol. 94 (2011)
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(7Z)-7-[(4-Methoxyphenyl)methylidene]furo[3,4-b]pyridin-5(7H)-one (3a) and 7-(4-Methoxyphen-
yl)-5H-pyrano[4,3-b]pyridin-5-one (3b). From 2-bromonicotinic acid (101 mg, 0.500 mmol) and 1-
ethynyl-4-methoxybenzene (99.0 mg, 0.750 mmol). CC (40% Et2O/petroleum ether): 3a (A: 56.0 mg,
44%; B: 55.0 mg, 43%) as an offwhite solid. Recrystallization from Et2O/petroleum ether gave off-white
crystals. M.p. 164 – 1658. IR: 1768 (C¼O). 1H-NMR (400 MHz, CDCl3): 3.87 (s, MeO); 6.94 (s,
ArCH¼C); 6.97 (d, J ¼ 7.0, HꢀC(3’), HꢀC(5’)); 7.44 (dd, J ¼ 8.0, 4.8, HꢀC(3)); 7.87 (d, J ¼ 7.0, HꢀC(2’),
HꢀC(6’)); 8.23 (dd, J ¼ 8.0, 1.6, HꢀC(4)); 8.90 (dd, J ¼ 4.8, 1.6, HꢀC(2)). 13C-NMR (100.6 MHz, CDCl3):
55.35 (MeO); 108.85 (ArCH¼C); 114.40 (C(3’,5’)); 117.00 (C); 123.64 (C(3)); 125.28 (C(1’)); 132.49
(C(2’,6’)); 133.77 (C(4)); 142.15 (C(7)); 156.04 (C(2)); 158.56 (C); 160.43 (MeOꢀC); 164.98 (C¼O). EI-
MS: 254.08 (17, [M þ 1]þ), 253.08 (100, Mþ), 252.08 (59, [M ꢀ 1]þ). HR-MS: 253.0741 (Mþ, C15H11NOþ3 ;
calc. 253.0739).
Compound 3b was isolated from CC (60% Et2O/petroleum ether): off-white solid (A: 33.0 mg, 26%;
B: 29.0 mg, 23%). Recrystallization from Et2O/petroleum ether gave off-white crystals. M.p. 178 – 1808
([7]: 177 – 1788). Spectroscopic data: already described in the lit. similar to the ones obtained in this
work.
(7Z)-7-[(2-Methoxyphenyl)methylidene]furo[3,4-b]pyridin-5(7H)-one (4a) and 7-(2-Methoxyphen-
yl)-5H-pyrano[4,3-b]pyridin-5-one (4b). From 2-bromonicotinic acid (101 mg, 0.500 mmol) and 1-
ethynyl-2-methoxybenzene (99.0 mg, 0.750 mmol). CC (40% Et2O/petroleum ether): 4a (A: 34.0 mg,
25%; B: 29.0 mg, 21%) as an off-white solid. Recrystallization from Et2O/petroleum ether gave off-white
crystals. M.p. > 3008 (dec.). IR: 1772 (C¼O). 1H-NMR (400 MHz, CDCl3): 3.93 (s, MeO); 6.93 – 6.95 (m,
1 arom. H); 7.04 – 7.08 (m, 1 arom. H); 7.33 – 7.37 (m, 1 arom. H); 7.46 (dd, J ¼ 8.0, 4.6, HꢀC(3)); 7.54 (s,
ArCH¼C); 8.24 (dd, J ¼ 8.0, 1.6, HꢀC(4)); 8.30 (dd, J ¼ 8.0, 1.6, HꢀC(6’)); 8.94 (dd, J ¼ 4.6, 1.6, HꢀC(2)).
13C-NMR (100.6 MHz, CDCl3): 55.59 (MeO); 103.03 (ArCH¼C); 110.62 (CH); 117.29 (C); 120.99 (CH);
121.44 (C); 123.82 (C(3)); 130.66 (CH); 131.66 (CH); 133.74 (C(4)); 143.51 (C(7)); 156.12 (C(2)); 157.90
(MeOꢀC); 158.72 (C); 165.04 (C¼O). EI-MS: 254.08 (2, [M þ 1]þ), 253.08 (10, Mþ), 252.06 (1, [M ꢀ
1]þ), 223.06 (14, [M ꢀ 30]þ), 222.05 (100, [M ꢀ MeO]þ). HR-MS: 253.0742 (Mþ, C15H11NOþ3 ; calc.
253.0739).
Compound 4b was isolated from CC (60% Et2O/petroleum ether): yellow pale solid (A: 51.0 mg,
40%; B: 52.0 mg, 41%). Recrystallization from Et2O/petroleum ether gave yellow pale crystals. M.p.
1
187 – 1898. IR: 1720 (C¼O). H-NMR (400 MHz, CDCl3): 3.99 (s, MeO); 7.03 – 7.12 (m, 2 arom. H);
7.41 – 7.46 (m, HꢀC(3), 1 arom. H); 7.72 (s, HꢀC(8)); 7.99 – 8.02 (m, 1 arom. H); 8.56 (dd, J ¼ 7.8, 1.6,
HꢀC(4)); 8.95 (br. s, HꢀC(2)). 13C-NMR (100.6 MHz, CDCl3): 55.60 (MeO); 108.65 (C(8)); 111.47
(CH); 117.02 (C); 120.01 (C); 120.83 (CH); 122.73 (C(3)); 128.93 (CH); 131.64 (CH); 137.49 (C(4));
154.21 (C(7)); 155.46 (C); 156.03 (C(2)); 157.70 (MeOꢀC); 162.21 (C¼O). EI-MS: 254.08 (16, [M þ 1]þ),
253.08 (100, Mþ), 226.08 (5, [M ꢀ 27]þ), 225.08 (32, [M ꢀ 28]þ). HR-MS: 253.0741 (Mþ, C15H11NOþ3 ;
calc. 253.0739).
(7Z)-7-[(3-Fluorophenyl)methylidene]furo[3,4-b]pyridin-5(7H)-one (5a) and 7-(3-Fluorophenyl)-
5H-pyrano[4,3-b]pyridin-5-one (5b). From 2-bromonicotinic acid (101 mg, 0.500 mmol) and 1-ethynyl-3-
fluorobenzene (90.0 mg, 0.750 mmol). CC (50% Et2O/petroleum ether): 5a (A: 51.0 mg, 40%; B:
48.0 mg, 38%) as a yellow pale solid. Recrystallization from Et2O/petroleum ether gave off-white
crystals. M.p. 174 – 1768. IR: 1736 (C¼O). 1H-NMR (300 MHz, CDCl3): 6.92 (s, ArCH¼C); 7.04 – 7.10 (m,
1 arom. H); 7.37 – 7.44 (m, HꢀC(5’)); 7.51 (dd, J ¼ 7.7, 4.7, HꢀC(3)); 7.61 – 7.69 (m, 2 arom. H); 8.26 (dd,
J ¼ 7.7, 1.7, HꢀC(4)); 8.94 (dd, J ¼ 4.7, 1.7, HꢀC(2)). 13C-NMR (75.4 MHz, CDCl3): 107.33 (d, J ¼ 2.9,
ArCH¼C); 116.07 (d, J ¼ 21.3, CH); 117.04 (d, J ¼ 22.8, CH); 117.52 (C); 124.44 (C(3)); 126.52 (d, J ¼ 2.9,
C(6’)); 130.24 (d, J ¼ 8.3, C(5’)); 133.83 (C(4)); 134.50 (d, J ¼ 8.3, C(1’)); 144.46 (C(7)); 156.31 (C(2));
158.34 (C); 161.26 (C); 164.48 (C); 164.52 (CꢀF, C¼O). EI-MS: 242.06 (8, [M þ 1]þ), 241.05 (54, Mþ),
240.05 (100, [M ꢀ 1]þ). HR-MS: 241.0539 (Mþ, C14H8FNOþ2 ; calc. 241.0539).
Compound 5b was isolated from CC (70% Et2O/petroleum ether): yellow pale solid (A: 27.0 mg,
21%; B: 23.0 mg, 18%). Recrystallization from Et2O/petroleum ether gave yellow pale crystals. M.p.
1
161 – 1638. IR: 1744 (C¼O). H-NMR (400 MHz, CDCl3): 7.17 – 7.22 (m, 1 arom. H); 7.25 (s, HꢀC(8));
7.46 – 7.50 (m, HꢀC(3), HꢀC(5’)); 7.62 – 7.66 (m, 1 arom. H); 7.71 – 7.73 (m, 1 arom. H); 8.57 (dd, J ¼ 7.8,
1.4, HꢀC(4)); 8.98 (br. s, HꢀC(2)). 13C-NMR (100.6 MHz, CDCl3): 104.55 (C(8)); 112.75 (d, J ¼ 24.1,
CH); 117.30 (C); 117.72 (d, J ¼ 21.1, CH); 121.28 (d, J ¼ 3.0, C(6’)); 123.24 (C(3)); 130.66 (d, J ¼ 8.0,

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Helvetica Chimica Acta – Vol. 94 (2011)
C(5’)); 133.53 (d, J ¼ 8.0, C(1’)); 137.61 (C(4)); 154.77 (C); 155.87 (C(7)); 156.41 (C(2)); 161.67 (C¼O);
162.03 (d, J ¼ 246.5, C(3’)). EI-MS: 242.06 (15, [M þ 1]þ), 241.06 (100, Mþ), 240.06 (5, [M ꢀ 1]þ), 213.06
(56, [M ꢀ 28]þ). HR-MS: 241.0543 (Mþ, C14H8FNOþ2 ; calc. 241.0539).
(7Z)-7-[(4-Fluorophenyl)methylidene]furo[3,4-b]pyridin-5(7H)-one (6a) and 7-(4-Fluorophenyl)-
5H-pyrano[4,3-b]pyridin-5-one (6b). From 2-bromonicotinic acid (101 mg, 0.500 mmol) and 1-ethynyl-4-
fluorobenzene (90.0 mg, 0.750 mmol). CC (50% Et2O/petroleum ether): 6a (A: 48.0 mg, 40%) as a
yellow pale solid. Recrystallization from Et2O/petroleum ether gave off-white crystals. M.p. 177 – 1798.
1
IR: 1739 (C¼O). H-NMR (400 MHz, CDCl3): 6.94 (s, ArCH¼C); 7.12 – 7.16 (m, HꢀC(3’), HꢀC(5’));
7.49 (dd, J ¼ 7.6, 4.8, HꢀC(3)); 7.89 – 7.92 (m, HꢀC(2’), HꢀC(6’)); 8.25 (dd, J ¼ 7.6, 1.6, HꢀC(4)); 8.93 (dd,
J ¼ 4.8, 1.6, HꢀC(2)). 13C-NMR (100.6 MHz, CDCl3): 107.55 (ArCH¼C); 116.04 (d, J ¼ 21.1, C(3’,5’));
117.30 (C); 124.17 (C(3)); 128.81 (d, J ¼ 3.0, C(1’)); 132.67 (d, J ¼ 8.0, C(2’,6’)); 133.81 (C(4)); 143.37
(C(7)); 156.26 (C(2)); 158.51 (C); 163.02 (d, J ¼ 251.5, CꢀF); 164.73 (C¼O). EI-MS: 242.06 (7, [M þ
1]þ), 241.05 (69, Mþ), 240.04 (100, [M ꢀ 1]þ). HR-MS: 241.0535 (Mþ, C14H8FNOþ2 ; calc. 241.0539).
Compound 6b was isolated from CC (70% Et2O/petroleum ether): off-white solid (A: 19.0 mg,
16%). Recrystallization from Et2O/petroleum ether gave off-white crystals. M.p. 171 – 1738. IR: 1739
1
(C¼O). H-NMR (400 MHz, CDCl3): 7.18 – 7.22 (m, HꢀC(3’), HꢀC(5’), HꢀC(8)); 7.44 (dd, J ¼ 7.6, 4.8,
HꢀC(3)); 7.91 – 7.95 (m, HꢀC(2’), HꢀC(6’)); 8.56 (dd, J ¼ 7.6, 2.0, HꢀC(4)); 8.95 (dd, J ¼ 4.8, 2.0,
HꢀC(2)). 13C-NMR (100.6 MHz, CDCl3): 103.44 (C(8)); 116.22 (d, J ¼ 22.0, C(3’,5’)); 116.82 (C); 122.92
(C(3)); 127.62 (d, J ¼ 3.0, C(1’)); 127.80 (d, J ¼ 9.0, C(2’,6’)); 137.61 (C(4)); 154.98 (C); 156.40 (C); 156.43
(C(2)); 161.85 (C¼O); 164.26 (d, J ¼ 251.5, CꢀF). EI-MS: 242.06 (14, [M þ 1]þ), 241.05 (100, Mþ), 214.05
(18, [M ꢀ 27]þ), 213.06 (84, [M ꢀ 28]þ). HR-MS: 241.0536 (Mþ, C14H8FNOþ2 ; calc. 241.0539).
(7Z)-7-[(2-Fluorophenyl)methylidene])furo[3,4-b]pyridin-5(7H)-one (7a) and 7-(2-Fluorophenyl)-
5H-pyrano[4,3-b]pyridin-5-one (7b). From 2-bromonicotinic acid (101 mg, 0.500 mmol) and 1-ethynyl-2-
fluorobenzene (90.0 mg, 0.750 mmol). CC (30% Et2O/petroleum ether): 7a (A: 55.0 mg, 45%; B:
55.0 mg, 45%) as a yellow pale solid. Recrystallization from Et2O/petroleum ether gave off-white
crystals. M.p. 199 – 2018. IR: 1744 (C¼O). 1H-NMR (400 MHz, CDCl3): 7.10 – 7.15 (m, HꢀC(3’)); 7.23 –
7.27 (m, 2 arom. H); 7.28 (s, ArCH¼C); 7.32 – 7.38 (m, 1 arom. H); 7.50 (dd, J ¼ 8.0, 4.8, HꢀC(3)); 8.25
(dd, J ¼ 8.0, 1.6, HꢀC(4)); 8.29 – 8.34 (m, HꢀC(5’)); 8.95 (dd, J ¼ 4.8, 1.6, HꢀC(2)). 13C-NMR
(100.6 MHz, CDCl3): 99.98 (d, J ¼ 8.0, ArCH¼C); 115.45 (d, J ¼ 22.0, C(3’)); 117.51 (C); 120.68 (d,
J ¼ 11.1, C); 124.37 (C(3)); 124.57 (d, J ¼ 8.0, CH); 130.73 (d, J ¼ 8.0, CH); 131.58 (d, J ¼ 2.0, C(5’));
133.75 (C(4)); 144.73 (d, J ¼ 2.0, C(7)); 156.34 (C(2)); 158.40 (C); 160.93 (d, J ¼ 253.5, CꢀF); 164.62
(C¼O). EI-MS: 242.06 (6, [M þ 1]þ), 241.05 (38, Mþ), 240.05 (33, [M ꢀ 1]þ), 223.06 (15, [M ꢀ 18]þ),
222.05 (100, [M ꢀ 19]þ). HR-MS: 241.0540 (Mþ, C14H8FNOþ2 ; calc. 241.0539).
Compound 7b was isolated from CC (40% Et2O/petroleum ether): off-white solid (A: 22.0 mg, 18%;
B: 13.0 mg, 11%). Recrystallization from Et2O/petroleum ether gave off-white crystals. M.p. 165 – 1678.
IR: 1746 (C¼O). 1H-NMR (400 MHz, CDCl3): 7.23 – 7.33 (m, HꢀC(3’), HꢀC(5’)); 7.43 – 7.49 (m,
HꢀC(3); HꢀC(8), 1 arom. H); 8.00 – 8.04 (m, 1 arom. H); 8.57 (dd, J ¼ 8.0, 1.6, HꢀC(4)); 8.98 (dd, J ¼
4.6, 1.6, HꢀC(2)). 13C-NMR (100.6 MHz, CDCl3): 108.94 (d, J ¼ 15.1, C(8)); 116.68 (d, J ¼ 23.1, C(3’));
117.26 (C); 119.68 (d, J ¼ 10.1, C); 123.23 (C(3)); 124.64 (d, J ¼ 4.0, C(5’)); 128.65 (CH); 132.02 (d, J ¼
9.1, CH); 137.52 (C(4)); 151.97 (d, J ¼ 5.0, C); 154.93 (C); 156.36 (C(2)); 160.33 (d, J ¼ 254.5, CꢀF);
161.70 (C¼O). EI-MS: 242.05 (16, [M þ 1]þ), 241.06 (100, Mþ), 240.04 (4, [M ꢀ 1]þ), 222.05 (9, [M ꢀ
19]þ), 214.06 (14, [M ꢀ 27]þ), 213.06 (88, [M ꢀ 28]þ). HR-MS: 241.0542 (Mþ, C14H8FNOþ2 ; calc.
241.0539).
(7Z)-7-{[4-(Dimethylamino)phenyl]methylidene}furo[3,4-b]pyridin-5(7H)-one (8a) and 7-[4-(Di-
methylamino)phenyl]-5H-pyrano[4,3-b]pyridin-5-one (8b). From 2-bromonicotinic acid (101 mg,
0.500 mmol) and 4-ethynyl-N,N-dimethylbenzenamine (109.0 mg, 0.750 mmol). CC (50% Et2O/petro-
leum ether): 8a (B: 32.0 mg, 24%) as a yellow solid. Recrystallization from Et2O/petroleum ether gave
yellow pale crystals. M.p. 166 – 1688. IR: 1734 (C¼O). 1H-NMR (400 MHz, CDCl3): 3.06 (s, Me2N); 6.76
(d, J ¼ 9.0, HꢀC(3’), HꢀC(5’)); 6.92 (s, ArCH¼C); 7.38 (dd, J ¼ 7.8, 4.8, HꢀC(3)); 7.82 (d, J ¼ 9.0,
HꢀC(2’), HꢀC(6’)); 8.21 (dd, J ¼ 7.8, 1.6, HꢀC(4)); 8.87 (dd, J ¼ 4.8, 1.6, HꢀC(2)). 13C-NMR (100.6 MHz,
CDCl3): 40.18 (Me2N); 110.05 (ArCH¼C); 112.10 (C(3’,5’)); 116.46 (C); 122.91 (C(3)); 132.51 (C(2’,6’));
133.63 (C); 133.68 (C(4)); 140.78 (C(7)); 150.71 (C); 155.96 (C(2)); 158.65 (C); 165.34 (C¼O). EI-MS:

Helvetica Chimica Acta – Vol. 94 (2011)
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267.11 ([M þ 1]þ, 16), 266.11 (100, Mþ), 265.10 (10, [M ꢀ 1]þ). HR-MS: 266.1056 (Mþ, C16H14N2Oþ2 ; calc.
266.1055).
Compound 8b was isolated from CC (60% Et2O/petroleum ether): yellow solid (B: 21.0 mg, 16%).
Recrystallization from Et2O/petroleum ether gave yellow pale crystals. M.p. 196 – 1988. IR: 1741 (C¼O).
1H-NMR (400 MHz, CDCl3): 3.07 (s, Me2N); 6.76 (d, J ¼ 7.0, HꢀC(3’), HꢀC(5’)); 7.04 (s, HꢀC(8)); 7.32
(dd, J ¼ 8.0, 4.6, HꢀC(3)); 7.81 (d, J ¼ 7.0, HꢀC(2’), HꢀC(6’)); 8.50 (dd, J ¼ 8.0, 1.8, HꢀC(4)); 8.87 (dd,
J ¼ 4.6, 1.8, HꢀC(2)). 13C-NMR (100.6 MHz, CDCl3): 40.12 (Me2N); 99.95 (C(8)); 111.76 (C(3’,5’));
115.94 (C); 118.38 (C); 121.66 (C(3)); 127.03 (C(2’,6’)); 137.60 (C(4)); 151.92 (C); 155.78 (C); 156.18
(C(2)); 158.42 (C(7)); 162.52 (C¼O). EI-MS: 267.11 (17, [M þ 1]þ), 266.11 (100, Mþ), 265.10 (18, [M ꢀ
1]þ). HR-MS: 266.1051 (Mþ, C16H14N2Oþ2 ; calc. 266.1055).
(7Z)-7-(Thiophen-3-ylmethylidene)furo[3,4-b]pyridin-5(7H)-one (9a). From 2-bromonicotinic acid
(101 mg, 0.500 mmol) and 3-ethynylthiophene (84.0 mg, 0.750 mmol). CC (50% Et2O/petroleum ether):
9a (A: 58.0 mg, 50%; B: 60.0 mg, 52%) as a brown solid. Recrystallization from Et2O/petroleum ether
gave beige crystals. M.p. 122 – 1238. IR (CHCl3): 1785 (C¼O). 1H-NMR (400 MHz, CDCl3): 7.03 (s,
ArCH¼C)); 7.38 – 7.40 (dd, J ¼ 2.8, 4.8, HꢀC(5’)); 7.46 (dd, J ¼ 7.6, 4.6, HꢀC(3)); 7.64 (dd, J ¼ 4.8, 1.2,
HꢀC(4’)); 7.83 – 7.84 (m, HꢀC(2’)); 8.23 (dd, J ¼ 7.6, 1.6, HꢀC(4)); 8.91 (dd, J ¼ 4.8, 1.6, HꢀC(2)).
13C-NMR (100.6 MHz, CDCl3): 103.08 (ArCH¼C); 117.56 (C); 123.91 (C(3)); 126.20 (C(5’)); 128.45
(C(2’)); 128.95 (C(4’)); 133.76 (C(4)); 133.79 (C); 142.80 (C(7)); 156.18 (C(2)); 158.37 (C); 164.63
(C¼O). EI-MS: 230.02 (17, [M þ 1]þ), 229.02 (95, Mþ), 228.01 (100, [M ꢀ 1]þ). HR-MS: 229.0197 (Mþ,
C12H7NO2Sþ; calc. 229.0198).
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Received February 8, 2011