Efficient palladium-catalyzed direct arylation of azines and diazines using ligand-free conditions

Article abstract of DOI:10.1016/j.tet.2009.02.025

The use of the palladium-catalyzed direct arylation was successfully tested on different electron-deficient heterocycles. The results demonstrate the effectiveness of the method based on the intramolecular coupling reaction providing polyazacyclic systems

Full text of DOI:10.1016/j.tet.2009.02.025

Tetrahedron 65 (2009) 3486–3491
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Efficient palladium-catalyzed direct arylation of azines and diazines
using ligand-free conditions
,
b
b
Luca Basolo a, Egle M. Beccalli a , Elena Borsini , Gianluigi Broggini
*
a
`
`
Istituto di Chimica Organica ‘A. Marchesini’, Facolta di Farmacia, Universita di Milano, via Venezian 21, 20133 Milano, Italy
Dipartimento di Scienze Chimiche e Ambientali, Universita dell’Insubria, via Valleggio 11, 22100 Como, Italy
b
`
a r t i c l e i n f o
a b s t r a c t
Article history:
The use of the palladium-catalyzed direct arylation was successfully tested on different electron-deficient
heterocycles. The results demonstrate the effectiveness of the method based on the intramolecular
coupling reaction providing polyazacyclic systems. This new application was obtained by using ligand-
free conditions with the mixture of Pd(OAc)2 and TBAC as catalytic system. With suitable substrates
different products arising from regioselective coupling were observed.
Received 5 November 2008
Received in revised form 9 January 2009
Accepted 13 February 2009
Available online 20 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
H3CO
N
Transition-metal mediated reactions are the most developed
method for the construction of aryl–aryl bonds. Among these cross-
coupling reactions are one of the most important tools. Recently
palladium-catalyzed direct arylation reactions have emerged as
attractive alternative to the mentioned methods,1 meaning with
this term the direct coupling of a non-activated aryl C–H bond with
an activated arene. The advantages of these reactions are that
simplified and readily available starting materials may be used
through the substitution of one of the functionalized arenes, nor-
mally the organometallic coupling partner, with a simple arene,
with an economical and practical advantage. Moreover the intra-
molecular version of the arylation reaction represents a very short
synthetic sequence to generate heterocycles of significant mole-
cular complexity as the poly(hetero)cyclic systems.
Besides the bi(hetero)aryl structural motif is a predominant
feature in many pharmaceutically relevant and biologically active
compounds. Some examples from recent literature are showed in
Figure 1.2
Our previous contribution in this area concerned the intra-
molecular direct arylations of electron-rich heterocycles bearing
both electron-withdrawing and electron-donor substituents in the
presence of a Pd(0)-catalyst, under different conditions (ligand or
ligand-free conditions).3 This process provides a straightforward
method to generate aza-substituted ring fused to (hetero)arenes.
In contrast to the numbers of papers reporting the utilization of
electron-rich heterocycles in the direct arylation process,4 both as
intra- and intermolecular reactions, the direct arylation of simple
O
N
N
N
N
H
N
N
N
c-Met Kinase inhibitor
H3 receptor agonist
Figure 1.
aromatic rings remains a significant challenge5 and even more the
use of electron-poor heterocycles, such as azines and diazines is
rare.6,7 In these cases the few reported results gave five- or six-
membered ring formation, in very low yields and following harsh
reaction conditions.6 Recently Fagnou and co-workers reported the
intermolecular arylations of azines and diazines exploiting the
transformation of these substrates on the more electron-rich azine-
and diazine N-oxides.7
In the present paper we report our studies on the direct aryla-
tion reactions of electron-poor heterocycles as azines and diazines.
We feel that the results are noteworthy due to the literature data
highlighting the poor reactivity of non-activated arenes.8
2. Results and discussion
Starting from nicotinic acids 1a,b and 3-quinolinecarboxylic acid
1c, the reaction with the 2-iodoaniline 2 followed by methylation
on the amides 3a–c, gave the corresponding tertiary amides 4a–c as
suitable substrates for the direct arylation reaction (Scheme 1). The
* Corresponding author. Tel.: þ39 02 50314479; fax: þ39 02 50314476.
E-mail address: egle.beccalli@unimi.it (E.M. Beccalli).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.025

L. Basolo et al. / Tetrahedron 65 (2009) 3486–3491
NaH (2.5 equiv.)
3487
O
O
COOH
MeI (3 equiv.)
1)SOCl2
R2
R1
R2
R2
R1
N
H
N
H2N
I
THF
r.t.
I
2)TEA,
CH2Cl2
r.t.
I
N
Me
R1
N
N
2
3a-c
4a-c
1a = R1, R2 = H
(58-97%)
(67-88%)
O
1b = R1 = Cl R2 = H
1c = R1-R2 = -(CH=)4-
Pd(OAc)2 (5 mol%)
Me
Me
R2
R1
N
AcOK (2 equiv.)
N
TBAC (1 equiv.)
R2
O
+
N
DMA, 100 °C
R1
N
5a-c (13-18%)
6a-c (45-62%)
Me
N
Me
X
H
X
Pd(OAc)2 (5 mol%)
AcOK (2 equiv.)
TBAC (1 equiv.)
COOH
NaH (2.5 equiv.)
MeI (3 equiv.)
O
N
N
O
O
Z
Z
1)SOCl2
THF
r.t.
2)TEA, CH2Cl2
DMA, 100 °C
Z
N
2 or H2N
N
N
11a,b
N
7
Br
N
8
10a,b
9a: Z = C (80%)
9b: Z = N (57%)
(58-69%)
(47-63%)
Scheme 1.
intramolecular process, obtained using Pd(OAc)2 as precatalyst,
AcOK as base, TBAC as additive and DMA as solvent, afforded two
regioisomers 5a–c and 6a–c arising from the cyclization on position
2 or 4 of the pyridyl ring, in 1:3 ratio in favour of the para position.9
Similarly the reaction of the isonicotinic acid 7 with 2-iodoaniline 2
or 2-bromo-3-aminopyridine 8 and subsequent methylation of 9a,b
afforded the amide 10a,b, which cyclization gave the tricyclic sys-
tems 11a,b. Usually direct arylation for rings of low reactivity ne-
cessitates the use of electron-rich and sterically hindered
triethylphosphines,10 however it should be noted that compared to
the procedure exploited previously, ligand-free conditions (Jeffery’s
conditions) have been successfully used. On the contrary, opti-
mizing the reaction conditions, we discovered that the presence of
the base and polar solvent is required to obtain the products. In fact
the absence of AcOK or solvent different than DMA or DMF, resulted
in unreacted substrate. The addition of TBAC improves the yields.
While temperatures higher than 100 ꢀC are used for similar re-
actions and in most cases heating for several hours to days is
necessary, the use of microwaves allowed considerably shortening
of the reaction time (45 min).
To probe the feasibility of the arylation reactions on electron-
poor heterocycles, we considered other substrates as the amides
arising from the 1,2-,1,3- and 1,4-diazines carboxylic acids 12–14. In
these cases, the amides 16–18 were obtained by reaction with 2-
iodo-N-methylaniline 15 on the unisolated acyl chloride. In fact the
methylation step carried out on the secondary amide must be
avoided giving methylation also on the heterocyclic nitrogen atom.
The cyclized products 19–21 were formed in one step from the
corresponding amides. In the case of amide 16, the cyclization re-
action gave two regioisomers 19a,b in 1:1 ratio, corresponding to
the cyclization product, respectively, on position 3 and 5 of the
pyridazyl ring, showing any selectivity in coupling reaction
(Scheme 2).
possible influence of the ring size on the cyclization process and
with the aim to obtain more challenging seven-membered rings,
we focused our attention on the homologous of pyridine carboxylic
acid, the pyridin-2-yl acetic acid 22 from which the corresponding
amide was prepared via unisolable acyl chloride in the presence of
triethylamine. The methylation step necessary to avoid the nitro-
gen coordination to palladium, gave in this case double methyl-
ation, involving benzylic carbon.
The tertiary amide 24 was then treated according to the repor-
ted conditions, to give the cyclized product 25 in good yield as
shown in Scheme 3.
The results obtained in terms of satisfactory yields for all the
cyclization processes allow us to comment on the mechanism in-
volved into the coupling reaction.
O
O
Me
C
N
C
N
B
A
N
B
A
OH
1) (COCl)2
Me
I
2)
H
N
I
A = N, B-C = C 12
B = N, A-C = C 13
C = N, A-B = C 14
16-18
15
(55-80%)
O
Pd(OAc)2 (5 mol%)
AcOK (2 equiv.)
TBAC (1 equiv.)
Me
C
B
A
N
DMA, 100 °C
N
19-21
(24-79%)
O
Me
Me
N
N
N
The choice to prepare specific polycyclic systems comes from
the pharmacological properties recently reported for benzonaph-
thyridines 5, 6 and 11 and pyrimidoquinolines 20, ranging from
antimalarial and antibacterial activities11 to properties as top-
oisomerase inhibitor and antitumor agents.12 To consider the
O
N
N
N
19b
Scheme 2.
19a

3488
L. Basolo et al. / Tetrahedron 65 (2009) 3486–3491
NaH
MeI
3. Conclusion
I
O
1)SOCl2
COOH
THF
N
2)TEA, CH2Cl2
The study has identified a practical and efficient direct arylation
reaction of electron-poor heterocycles using ligand-free conditions,
providing a straightforward synthesis of azapolycyclic systems.
Compared to other metal-catalyzed reactions the method offers the
advantage of simplified starting materials performing the synthesis
in only two steps, using ligand-free conditions, with an economical
benefit. Further research to extend these coupling reactions to in-
termolecular processes is currently underway.
N
N
H
H2N
22
23 (53%)
I
2
Pd(OAc)2 (5 mol%)
AcOK (2 equiv. )
TBAC (1 equiv.)
I
O
Me
N
N
N
N
DMA, 100 °C
4. Experimental
4.1. General
O
Me Me
Me
25 (90%)
24 (75%)
Scheme 3.
Melting points were determined on a Bu¨chi B-540 heating ap-
paratus and are uncorrected. 1H NMR and 13C NMR spectra were
obtained on an AVANCE Bruker 400 MHz in CDCl3 as solvent.
Chemical shifts are given in parts per million downfield from SiMe4.
13C NMR spectra are 1H-decoupled and the determination of the
multiplicities was achieved by the APT pulse sequence. IR spectra
were recorded on a Jasco FT/IR 5300 spectrophotometer.
Several pathways have been proposed for the palladium-cata-
lyzed arylation of aromatic compounds, the process depending on
the (hetero)aromatic substrate, base, ligand and solvent used. The
involvement of an electrophilic aromatic substitution (SEAr) was
commonly accepted for
p
-electron-rich substrates,1b,4e,h while
other mechanisms such as Heck-type process,4k or proton-ab-
straction13 could be envisaged for different substrates. In all the
proposed mechanisms, the first step generally occurs via oxidative
addition of the aryl halide to the transition metal to give the in-
termediate A, followed by different possible carbon–carbon bond
formation paths (Fig. 2). The electrophilic aromatic substitution
(SEAr) suggested for electron-rich heterocyclic substrates, through
the intermediate B gave the palladacycle structure D, which in turn
gives the cyclized product via reductive elimination with the con-
temporary Pd(0) catalyst regeneration. This hypothesis is not ap-
plicable in the case of electron-deficient heterocyclic nucleus.
Recent work indicated that Heck-type process is rather unlikely,14
and the literature data showed as a more probable mechanism the
concerted proton-abstraction path (by the halogen anion or by an
external base) operating via a four-membered transition state as
showed for the intermediate C.13 Support for the latter mechanism
was proven through the comparison of two different arenes and the
observation that the more electron-deficient substrate reacted
preferentially.15 This outcome is inconsistent with an SEAr
mechanism.
4.2. General procedure for the synthesis of the heteroamides
3a–c, 9a,b and 23
A mixture of acids 1a–c, 7 or 22 (10 mmol) and SOCl2 (10 mL,
137 mmol) was stirred at 100 ꢀC for 2.5 h. After evaporation of the
solvent, the residue was dissolved with CH2Cl2 (20 mL). A solution
of 2 or 8 (15 mmol) and TEA (2.1 mL,15 mmol) in CH2Cl2 (5 mL) was
added dropwise at 0 ꢀC. After stirring for 5 h at room temperature,
the solution was washed with 5% HCl (2ꢁ20 mL) and then with 5%
aqueous NaOH (2ꢁ20 mL). The organic layer was dried (Na2SO4)
and the solvent evaporated under reduced pressure. The residue
was chromatographed on a silica gel column, using CH2Cl2as eluent,
to give compounds 3, 9 and 23.
4.2.1. N-(2-Iodophenyl)-pyridine-3-carboxamide (3a)
White solid, mp 134–136 ꢀC; yield 67%. IR (Nujol): 3300,
1631 cmꢂ1
.
1H NMR:
d
6.92 (1H, dd, J¼5.0, 7.5 Hz), 7.41 (1H, dd,
J¼7.5, 7.8 Hz), 7.48 (1H, dd, J¼5.0, 7.5 Hz), 7.83 (1H, d, J¼7.8 Hz),
8.27–8.30 (1H, m), 8.32 (1H, br s, exch. D2O), 8.33–8.39 (1H, m),
8.80 (1H, d, J¼5.0 Hz), 9.22 (1H, s). 13C NMR:
d 91.1 (s), 122.6 (d),
124.1 (d), 127.0 (d), 129.8 (d), 130.6 (s), 135.6 (d), 138.1 (s), 139.3 (d),
148.5 (d), 153.2 (d), 163.8 (s). Anal. Calcd for C12H9IN2O (324.12): C,
44.47; H, 2.80; N, 8.64. Found: C, 44.34; H, 2.79; N, 8.80.
Pd(0)
X
Pd(0)
4.2.2. N-(2-Iodophenyl)-6-chloro-pyridine-3-carboxamide (3b)
White solid, mp 142–144 ꢀC; yield 88%. IR (Nujol): 3280,
1638 cmꢂ1 1H NMR:
. d 6.88–6.96 (1H, m), 7.38–7.46 (1H, m), 7.49
(1H, dd, J¼0.6, 8.4 Hz), 7.82 (1H, dd, J¼1.3, 8.1 Hz), 8.20 (1H, br s,
exch. D2O), 8.22 (1H, dd, J¼2.6, 8.4 Hz), 8.34 (1H, dd, J¼1.3, 8.1 Hz),
8.98 (1H, dd, J¼0.6, 2.6 Hz). 13C NMR:
d
90.9 (s), 122.3 (d), 124.9 (d),
-HX
+
127.0 (d), 129.4 (s), 129.8 (d), 137.7 (s), 138.2 (d), 139.2 (d), 148.6 (d),
155.2 (s), 162.6 (s). Anal. Calcd for C12H8ClIN2O (358,56): C, 40.20;
H, 2.25; N, 7.81. Found: C, 40.06; H, 2.36; N, 7.94.
Pd
X
Pd
Pd
H
X-
D
A
B
4.2.3. N-(2-Iodophenyl)-quinoline-3-carboxamide (3c)
-HX
Light brown solid, mp 221–222 ꢀC dec; yield 76%. IR (Nujol):
3290, 1640 cmꢂ1. 1H NMR:
d 6.95–7.03 (1H, m), 7.39–7.47 (1H, m),
δ+
7.82–7.90 (2H, m), 8.00–8.09 (2H, m), 8.18 (1H, d, J¼8.4 Hz), 8.64
(1H, d, J¼8.4 Hz), 9.27–9.28 (1H, m), 9.71 (1H, br s), 10.05 (1H, s). 13C
Pd
X
H
NMR:
d 91.5 (s), 123.0 (d), 127.1 (d), 127.3 (s), 127.5 (s), 128.5 (d),
δ−
128.6 (d), 129.3 (d), 129.7 (d), 132.7 (d), 137.9 (d), 138.1 (s), 139.2 (d),
147.5 (d), 148.1 (s), 163.3 (s). Anal. Calcd for C16H11IN2O (374.18): C,
51.36; H, 2.96; N, 7.49. Found: C, 51.30; H, 3.10; N, 7.56.
C
Figure 2.

L. Basolo et al. / Tetrahedron 65 (2009) 3486–3491
3489
4.2.4. N-(2-Iodophenyl)-pyridine-4-carboxamide16 (9a)
4.3.4. N-(2-Iodophenyl)-N-methyl-pyridine-4-carboxamide (10a)
White solid, mp 80–82 ꢀC (diisopropyl ether); yield 63%. IR
(Nujol): 1623 cmꢂ1 1H NMR:
3.38 (3H, s), 6.94 (1H, ddd, J¼1.8,
White solid, mp 122–124 ꢀC (lit. mp 122–123 ꢀC); yield 80%.
.
d
4.2.5. N-(2-Bromopyridin-3-yl)-pyridine-4-carboxamide (9b)
7.6, 8.0 Hz), 7.12 (1H, dd, J¼1.4, 7.8 Hz), 7.20–7.29 (3H, m), 7.79
White solid, mp 139–141 ꢀC; yield 57%. IR (Nujol): 3298,
(1H, dd, J¼1.2, 8.0 Hz,), 8.39–8.46 (2H, m). 13C NMR:
d 37.4 (q), 99.1
1623 cmꢂ1
.
1H NMR:
d
7.35 (1H, dd, J¼4.5, 8.1 Hz), 7.82–7.71 (2H,
(s), 122.2 (d), 129.8 (d), 129.9 (d), 130.1 (d), 130.2 (d), 140.5 (d),
140.7 (d), 143.4 (s), 145.9 (s), 149.7 (d), 168.4 (s). Anal. Calcd for
C13H11IN2O (338.15): C, 46.18; H, 3.28; N, 8.28. Found: C, 46.34; H,
3.11; N, 8.21.
overlapping), 8.17 (1H, dd, J¼1.5, 4.5 Hz), 8.54 (1H, br s, exch. D2O),
8.81 (1H, dd, J¼1.5, 8.1 Hz), 8.80–8.94 (2H, overlapping). 13C NMR:
d
121.1 (d), 124.1 (d), 124.2 (d), 129.3 (d), 133.4 (s), 134.0 (s), 141.1
(s), 145.7 (d), 145.8 (d), 151.4 (d), 164.0 (s). Anal. Calcd for
C11H8BrN3O (278.11): C, 47.51; H, 2.90; N, 15.11. Found: C, 47.63; H,
3.07; N, 15.22.
4.3.5. N-(2-Bromopyridin-3-yl)-N-methyl-pyridine-4-
carboxamide (10b)
White solid, mp 119–121 ꢀC (diisopropyl ether); yield 47%. IR
4.2.6. N-(2-Iodophenyl)-2-pyridin-2-yl-acetamide (23)
(Nujol): 1623 cmꢂ1. 1H NMR:
d 3.40 (3H, s), 7.18–7.35 (3H, m), 7.41
White solid, mp 110–112 ꢀC; yield 53%. IR (Nujol): 3258,
(1H, d, J¼7.2 Hz), 8.25 (1H, br s), 8.42–8.55 (2H, m). 13C NMR:
d 37.4
1632 cmꢂ1
.
1H NMR:
d
3.96 (2H, s), 6.82 (1H, dd, J¼7.5, 7.6 Hz),
(q), 99.8 (s), 123.2 (d), 129.7 (d), 129.9 (d), 130.3 (d), 130.6 (d), 141.5
(d), 142.7 (d), 144.6 (s), 146.9 (s), 168.4 (s). Anal. Calcd for
C12H10BrN3O (292.14): C, 49.34; H, 3.45; N, 14.38. Found: C, 49.49;
H, 3.51; N, 14.22.
7.26–7.35 (3H, m) 7.73 (1H, dd, J¼7.8, 8.2 Hz), 7.78 (1H, d,
J¼7.8 Hz), 8.24 (1H, d, J¼8.2 Hz), 8.70 (1H, d, J¼4.2 Hz), 9.88
(1H, s, exch. with D2O). 13C NMR:
d 46.4 (t), 89.7 (s), 122.7 (d),
122.8 (d), 124.5 (d), 126.2 (d), 129.3 (d), 137.9 (d), 138.4 (s),
139.5 (d), 149.7 (d), 155.2 (s), 167.9 (s). Anal. Calcd for
C13H11IN2O (338.15): C, 46.18; H, 3.28; N, 8.28. Found: C, 46.30;
H, 3.31; N, 8.20.
4.3.6. N-(2-Iodophenyl)-N-methyl-2-pyridin-2-yl-
propionamide (24)
White solid, mp 82–84 ꢀC; yield 75%. IR (Nujol): 1622 cmꢂ1. 1H
NMR:
d
1.50 (3H, d, J¼6.8 Hz), 3.21 (3H, s), 3.65 (1H, q, J¼6.8 Hz),
6.72 (1H, d, J¼7.7 Hz), 7.01 (1H, dd, J¼7.5, 7.7 Hz), 7.07–7.15 (3H, m),
4.3. General procedure for the synthesis of the N-methyl-
heteroamides 4a–c, 10a,b and 24
7.56 (1H, dd, J¼7.6, 7.7 Hz), 7.93 (1H, d, J¼7.8 Hz), 8.41 (1H, br s). 13C
NMR: d 19.6 (q), 36.9 (d), 47.3 (q),100.3 (s),122.0 (d),129.5 (d),129.7
(d), 130.1 (d), 130.2 (d), 137.0 (d), 140.3 (d), 145.8 (s), 149.3 (d), 161.5
(s), 173.0 (s). Anal. Calcd for C15H15IN2O (366.20): C, 49.20; H, 4.13;
N, 7.65. Found: C, 49.34; H, 4.31; N, 7.60.
To a stirred solution of 3, 9 or 23 (2 mmol) in dry THF (15 mL)
cooled to 0 ꢀC, 60% NaH (0.2 g, 5 mmol) was added under nitrogen
atmosphere. The resulting mixture was allowed to warm to rt; then
a solution of MeI (0.37 mL, 6 mmol) in dry THF (5 mL) was added
dropwise. After 4 h the solvent was evaporated and the residue
diluted with 1 M HCl (20 mL) and extracted with Et2O (2ꢁ20 mL).
The organic layer was dried with Na2SO4 and solvent evaporated
under reduced pressure. The residue was chromatographed on
a silica gel column, eluent CH2Cl2/AcOEt 3:1.
4.4. General procedure for the synthesis of amides 16–18
The acid 12, 13 or 14 (0.124 g, 1 mmol) was suspended in DME
(dimethoxyethane) (8 mL), cooled at 0 ꢀC under nitrogen atmo-
sphere.
A solution of N-methyl-2-iodoaniline (15) (0.28 g,
1.2 mmol) in DME (4 mL) was dropped then a solution of DMC (2-
chloro-1,3-dimethylimidazolium chloride) (0.169 g, 1 mmol) in
CH2Cl2 (3 mL) and finally a solution of TEA (280 mL, 2 mmol) in
CH2Cl2 (3 mL) was added. The reaction mixture was stirred for 1 h
at 0 ꢀC then allowed to warm to rt and left to react overnight. The
mixture was then diluted with 300 mL of AcOEt and washed with
30 mL water, 30 mL of a saturated solution of NaHCO3, 30 mL of
water and 30 mL of brine. The organic layer was dried with Na2SO4
and the solvent evaporated under reduced pressure. The residue
was chromatographed on a silica gel, eluent AcOEt, to give com-
pounds 16–18.
4.3.1. N-(2-Iodophenyl)-N-methyl-pyridine-3-carboxamide (4a)
White solid, mp 117–118 ꢀC; yield 58%. IR (Nujol): 1641 cmꢂ1. 1H
NMR:
7.69–7.81 (2H, overlapping), 8.39–8.56 (2H, overlapping). 13C NMR:
37.4 (q), 99.9 (s), 123.2 (d), 129.5 (d), 129.9 (d), 130.2 (d), 130.4 (d),
d 3.39 (3H, s), 6.92–6.96 (1H, m), 7.05–7.36 (3H, overlapping),
d
140.8 (d), 141.7 (d), 143.4 (s), 145.9 (s), 148.7 (d), 165.3 (s). Anal.
Calcd for C13H11IN2O (338.15): C, 46.18; H, 3.28; N, 8.28. Found: C,
46.30; H, 3.10; N, 8.31.
4.3.2. N-(2-Iodophenyl)-N-methyl-6-chloro-pyridine-3-
carboxamide (4b)
White solid, mp 114–115 ꢀC; yield 95%. IR (Nujol): 1627 cmꢂ1. 1H
4.4.1. N-(2-Iodophenyl)-N-methyl-pyridazine-4-carboxamide (16)
NMR:
d
3.38 (3H, s), 6.94–7.02 (1H, m), 7.14–7.22 (2H, m), 7.27–7.36
Light amber-coloured solid, mp 166–168 ꢀC; yield 70%. IR
(1H, m), 7.69 (1H, dd, J¼2.4, 8.2 Hz), 7.81 (1H, dd, J¼1.3, 8.0 Hz), 8.3
(Nujol): 1636 cmꢂ1. 1H NMR:
d
3.38 (3H, s), 6.96–7.04 (1H, m), 7.20–
7.36 (3H, m), 7.75–7.79 (1H, m), 9.06 (1H, s), 9.05 (1H, s). 13C NMR:
37.6 (q), 99.2 (s), 124.7 (d), 130.0 (d), 130.3 (d), 130.7 (d), 133.9 (s),
(1H, d, J¼2.4 Hz). 13C NMR:
d 37.8 (q), 99.3 (s), 123.7 (d), 130.0 (d),
130.1 (d), 130.2 (d), 130.7 (d), 139.0 (d), 140.8 (s), 146.1 (s), 149.6 (d),
152.6 (s), 167.3 (s). Anal. Calcd for C13H10ClIN2O (372.59): C, 41.91;
H, 2.71; N, 7.52. Found: C, 42.06; H, 2.58; N, 7.61.
d
140.8 (d), 145.0 (s), 149.5 (d), 151.1 (d), 165.8 (s). Anal. Calcd for
C12H10IN3O (339.13): C, 42.50; H, 2.97; N, 12.39. Found: C, 42.36; H,
3.09; N, 12.22.
4.3.3. N-(2-Iodophenyl)-N-methyl-quinoline-3-carboxamide (4c)
Light orange solid, mp 163–161 ꢀC; yield 97%. IR (Nujol):
4.4.2. N-(2-Iodophenyl)-N-methyl-pyrimidine-5-carboxamide (17)
1632 cmꢂ1. 1H NMR:
d
3.39 (3H, s), 6.79–6.88 (1H, m), 7.19–7.21 (2H,
White solid, mp 97–98 ꢀC; yield 80%. IR (Nujol): 1630 cmꢂ1
.
m), 7.39–7.47 (1H, m), 7.59–7.72 (3H, m), 7.93 (1H, d, J¼8.6 Hz), 8.15
1H NMR:
7.75–7.80 (1H, m), 8.64 (2H, s), 9.00 (1H, s). 13C NMR:
d
d
3.36 (3H, s), 6.92–7.00 (1H, m), 7.21–7.36 (2H, m),
37.7 (q),
(1H, d, J¼1.4 Hz), 8.82 (1H, s). 13C NMR:
d
37.9 (q), 99.5 (s), 126.7 (s),
127.3 (d), 128.7 (d), 129.0 (s), 129.3 (d), 129.9 (d), 130.0 (d), 130.2 (d),
130.3 (d), 136.9 (d), 140.6 (d), 146.4 (s), 148.1 (s), 149.5 (d), 168.4 (s).
Anal. Calcd for C17H13IN2O (388.20): C, 52.60; H, 3.38; N, 7.22.
Found: C, 52.77; H, 3.29; N, 7.29.
99.4 (s), 129.9 (s), 130.0 (d), 130.2 (d), 130.5 (d), 140.8 (d), 145.5
(s), 156.4 (2d), 159.1 (d), 165.7 (s). Anal. Calcd for C12H10IN3O
(339.13): C, 42.50; H, 2.97; N, 12.39. Found: C, 42.39; H, 3.08; N,
12.27.

3490
L. Basolo et al. / Tetrahedron 65 (2009) 3486–3491
4.4.3. N-(2-Iodophenyl)-N-methyl-pyrazine-2-carboxamide (18)
Pearl grey solid, mp 94–96 ꢀC; yield 55%. IR (Nujol): 1640 cmꢂ1
1H NMR:
3.42 (3H, s), 6.90–7.01 (1H, m), 7.26–7.36 (2H, m), 7.74–
7.80 (1H, m), 8.16–8.19 (1H, m), 8.40 (1H, d, J¼2.6 Hz), 8.97 (1H, s).
13C NMR:
37.6 (q), 99.3 (s), 129.4 (d), 129.6 (d), 130.2 (d), 139.9 (d),
4.5.5. 5-Methyl-dibenzo[b,h][1,6]naphthyridin-6-(5H)-one (5c)18
.
Light yellow solid, mp 214–216 ꢀC (lit. mp not reported); yield
d
16%. IR (Nujol): 1630 cmꢂ1. 1H NMR:
d
3.84 (3H, s), 7.39–7.47 (2H,
m), 7.58–7.71 (2H, m), 7.84–7.93 (1H, m), 8.05–8.09 (1H, m), 8.25–
8.29 (1H, m), 9.10–9.15 (1H, m), 9.35 (1H, s). 13C NMR:
30.1 (q),
d
d
142.5 (d), 145.1 (d), 145.5 (d), 146.1 (s), 149.3 (s), 166.3 (s). Anal.
Calcd for C12H10IN3O (339.13): C, 42.50; H, 2.97; N, 12.39. Found: C,
42.37; H, 3.09; N, 12.28.
114.9 (d), 119.8 (s), 121.3 (s), 123.2 (d), 126.1 (d), 126.9 (d), 127.5 (s),
129.4 (d), 129.6 (d), 131.8 (d), 132.3 (d), 139.0 (d), 139.9 (s), 149.5 (s),
150.5 (s), 162.2 (s). Anal. Calcd for C17H12N2O (260.29): C, 78.44; H,
4.65; N, 10.76. Found: C, 78.55; H, 4.64; N, 10.68.
4.5. General procedure for the cyclization of amides 4, 10, 16–
18 and 24
4.5.6. 5-Methyl-dibenzo[c,f][2,7]naphthyridin-6-(5H)-one (6c)19
Cream solid, mp 211–213 ꢀC (lit. mp 217–218 ꢀC); yield 45%. IR
(Nujol): 1639 cmꢂ1 1H NMR:
. d 3.83 (3H, s), 7.36–7.45 (1H, m),
A solution of 4a–c or 10a,b or 16–18 or 24 (1 mmol), Pd(OAc)2
(0.011 g, 0.05 mmol), AcOK (0.196 g, 2 mmol) and Bu4NCl (0.278 g,
1 mmol) in DMA (8 mL) was stirred at 100 ꢀC for 24 h. For com-
pounds 4a–c and 16–18 the cyclization was performed by micro-
waves irradiation for 45 min at 120 ꢀC at 300 W. After cooling to
room temperature, the mixture was diluted with brine (15 mL) and
extracted with Et2O (3ꢁ30 mL). The organic layer was dried with
Na2SO4 and solvent evaporated under reduced pressure. The resi-
due was chromatographed on a silica gel column, eluent hexane/
AcOEt 2:1, to give the cyclized product. In the case of amides 4a–c
the two regioisomers 5a–c and 6a–c were isolated, in ratio 1:3
nearly.
7.51–7.55 (1H, m), 7.66–7.75 (2H, m), 7.82–7.91 (1H, m), 8.26–8.31
(1H, m), 8.67 (1H, d, J¼8.6 Hz), 8.79 (1H, d, J¼8.6 Hz), 9.85 (1H, s).
13C NMR:
d 30.4 (q), 115.5 (d), 118.1 (s), 118.3 (s), 122.6 (s), 122.7
(d), 127.2 (d), 127.6 (d), 129.7 (d), 130.8 (d), 130.9 (d), 131.6 (d),
138.9 (s), 140.3 (s), 150.1 (s), 150.3 (d), 161.2 (s). Anal. Calcd for
C17H12N2O (260.29): C, 78.44; H, 4.65; N, 10.76. Found: C, 78.29; H,
4.79; N, 10.92.
4.5.7. 6-Methyl-6H-benzo[c][2,6]naphthyridin-5-one (11a)16
White solid, mp 192–194 ꢀC (lit. mp 197–199 ꢀC); yield 58%. IR
(Nujol): 1659 cmꢂ1
.
1H NMR:
d
3.74 (3H, s), 7.32 (1H, dd, J¼7.5,
7.8 Hz), 7.37 (1H, d, J¼7.8 Hz), 7.56 (1H, dd, J¼7.5, 8.0 Hz), 8.19 (1H,
d, J¼5.1 Hz), 8.28 (1H, d, J¼8.0 Hz), 8.75 (1H, d, J¼5.1 Hz), 9.58 (1H,
4.5.1. 6-Methyl-benzo[h][1,6]naphthyridin-5-(6H)-one (5a)17
s). 13C NMR:
d 30.5 (q), 115.6 (d), 117.4 (s), 117.5 (s), 121.0 (d), 123.0
White solid, mp 169–171 ꢀC (lit. mp 173–175 ꢀC); yield 18%.
(d), 123.5 (d), 128.0 (s), 130.8 (d), 138.5 (s), 145.8 (d), 148.3 (d), 160.5
(s). Anal. Calcd for C13H10N2O (210.24): C, 74.27; H, 4.79; N, 13.32.
Found: C, 74.39; H, 4.87; N, 13.43.
IR (Nujol): 1630 cmꢂ1 1H NMR:
. d 3.82 (3H, s), 7.36–7.46 (2H,
m), 7.51 (1H, dd, J¼4.6, 8.1 Hz), 7.60–7.69 (1H, m), 8.77 (1H,
dd, J¼1.8, 8.1 Hz), 8.90 (1H, dd, J¼1.8, 7.9 Hz), 9.00 (1H, dd,
J¼1.8, 4.6 Hz). 13C NMR:
d
30.1 (q), 114.8 (d), 120.9 (s), 123.1
4.5.8. 6-Methyl-6H-pyrido[2,3-f][2,6]naphthyridin-5-one (11b)
(d), 123.2 (d), 125.5 (d), 129.2 (s), 131.6 (d), 137.0 (d), 139.4 (s),
150.5 (s), 153.9 (d), 161.9 (s). Anal. Calcd for C13H10N2O
(210.23): C, 74.27; H, 4.79; N, 13.33. Found: C, 74.39; H, 4.86;
N, 13.24.
White solid, mp 215–218 ꢀC (diisopropyl ether); yield 69%. IR
(Nujol): 1630 cmꢂ1
.
1H NMR:
d
3.81 (3H, s), 7.54 (1H, dd, J¼4.4,
8.5 Hz), 7.74 (1H, d, J¼8.5 Hz), 8.26 (1H, d, J¼5.1 Hz), 8.66 (1H, d,
J¼4.4 Hz), 8.93 (1H, d, J¼5.1 Hz), 10.18 (1H, s). 13C NMR:
d 30.1 (q),
120.5 (d), 122.4 (d), 124.8 (d), 128.7 (s), 132.3 (s), 134.8 (s), 136.4 (s),
144.8 (d), 148.2 (d), 150.1 (d), 160.3 (s). Anal. Calcd for C12H9N3O
(211.22): C, 68.24; H, 4.29; N, 19.89. Found: C, 68.39; H, 4.11; N,
19.96.
4.5.2. 6-Methyl-benzo[c][2,7]naphthyridin-5-(6H)-one (6a)17
White solid, mp 188–191 ꢀC (lit. mp 194–196 ꢀC); yield 62%. IR
(Nujol) 1662 cmꢂ1. 1H NMR:
d 3.80 (3H, s), 7.25–7.46 (2H, m), 7.67
(1H, dd, J¼7.6, 7.8 Hz), 8.03 (1H, d, J¼5.6 Hz), 8.27 (1H, d,
J¼7.6 Hz), 8.88 (1H, d, J¼5.6 Hz), 9.72 (1H, s). 13C NMR:
d
29.9 (q),
4.5.9. 6-Methyl-pyridazino[4,5-c]quinolin-5-(6H)-one (19a)
115.5 (d), 117.4 (s), 123.0 (d), 124.2 (d), 129.7 (d), 130.2 (s), 131.9
(d), 136.0 (d), 139.9 (s), 140.0 (s), 140.6 (d), 168.3 (s). Anal. Calcd for
C13H10N2O (210.23): C, 74.27; H, 4.79; N, 13.32. Found: C, 74.43; H,
4.90; N, 13.22.
Cream solid, mp 250–252 ꢀC; yield 28%. IR (Nujol): 1626 cmꢂ1
.
1H NMR:
d 3.85 (3H, s), 7.44–7.55 (2H, m), 7.74–7.83 (1H, m), 8.39–
8.44 (1H, m), 10.01 (1H, d, J¼1.2 Hz), 10.10 (1H, d, J¼1.2 Hz). 13C
NMR:
d 30.5 (q), 114.8 (s), 115.9 (d), 120.0 (s), 123.9 (d), 124.0 (d),
129.8 (s), 133.5 (d), 140.8 (s), 145.9 (d), 149.2 (d), 159.3 (s). Anal.
Calcd for C12H9N3O (211.22): C, 68.24; H, 4.29; N, 19.89. Found: C,
68.37; H, 4.33; N, 19.75.
4.5.3. 2-Chloro-6-methylbenzo[h][1,6]naphthyridin-5-(6H)-
one (5b)
White solid, mp 170–172 ꢀC; yield 13%. IR (Nujol): 1625 cmꢂ1. 1H
NMR:
d
3.80 (3H, s), 7.38–7.44 (2H, m), 7.48 (1H, d, J¼8.2 Hz), 7.62–
4.5.10. 6-Methyl-pyridazino[4,3-c]quinolin-5-(6H)-one (19b)
7.77 (1H, m), 8.68 (1H, d, J¼8.2 Hz), 8.81 (1H, dd, J¼1.3, 7.9 Hz). 13C
Light yellow solid, mp 200–202 ꢀC; yield 24%. IR (Nujol):
NMR:
d
30.0 (q), 114.8 (d), 115.7 (s), 119.9 (s), 123.3 (d), 124.0 (d),
1630 cmꢂ1. 1H NMR:
d
3.83 (3H, s), 7.45–7.53 (2H, m), 7.70–7.78 (1H,
m), 8.39 (1H, d, J¼5.3 Hz), 9.20–9.25 (1H, m), 9.55 (1H, d, J¼5.3 Hz).
13C NMR:
30.4 (q), 115.1 (d), 118.3 (s), 121.5 (s), 124.0 (d), 124.2 (d),
125.9 (d), 132.3 (d), 139.9 (d), 151.1 (s), 153.0 (s), 155.9 (s), 161.1 (s).
Anal. Calcd For C13H9ClN2O (244.68): C, 63.81; H, 3.71; N, 11.45.
Found: C, 63.98; H, 3.89; N, 11.40.
d
125.5 (d), 132.8 (d), 139.4 (s), 150.6 (d), 151.0 (s), 160.6 (s). Anal.
Calcd for C12H9N3O (211.22): C, 68.24; H, 4.29; N, 19.89. Found: C,
68.33; H, 4.36; N, 19.80.
4.5.4. 2-Chloro-6-methylbenzo[c][2,7]naphthyridin-5-(6H)-
one (6b)
White solid, mp 212–214 ꢀC; yield 48%. IR (Nujol): 1635 cmꢂ1. 1H
4.5.11. 6-Methyl-pyrimido[5,4-c]quinolin-5-(6H)-one (20)
NMR:
d
3.80 (3H, s), 7.34–7.47 (2H, m), 7.66–7.75 (1H, m), 8.07 (1H,
White solid, mp 190–192 ꢀC; yield 79%. IR (Nujol): 1628 cmꢂ1. 1H
s), 8.20 (1H, dd, J¼1.3, 8.1 Hz), 9.50 (1H, s). 13C NMR:
d
30.0 (q), 115.4
NMR:
d
3.36 (3H, s), 6.92–7.00 (1H, m), 7.21–7.36 (2H, m), 7.75–7.80
29.9 (q),115.0 (d), 117.9
(d), 115.8 (d), 116.5 (s), 119.6 (s), 123.3 (d), 124.4 (d), 132.9 (d), 140.1
(s), 142.5 (s), 153.0 (d), 154.9 (s), 160.4 (s). Anal. Calcd for
C13H9ClN2O (244.68): C, 63.81; H, 3.71; N, 11.45. Found: C, 63.92; H,
3.80; N, 11.38.
(1H, m), 8.64 (1H, s), 9.00 (1H, s). 13C NMR:
d
(s), 118.8 (s), 123.4 (d), 125.9 (d), 133.9 (d), 141.1 (s), 155.9 (s), 159.4
(d), 160.4 (s), 160.9 (d). Anal. Calcd for C12H9N3O (211.22): C, 68.24;
H, 4.29; N, 19.89. Found: C, 68.35; H, 4.35; N, 19.77.

L. Basolo et al. / Tetrahedron 65 (2009) 3486–3491
3491
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4.5.12. 6-Methyl-pyrazino[2,3-c]quinolin-5-(6H)-one (21)
Ivory-coloured solid, mp 195–197 ꢀC; yield 49%. IR (Nujol):
1633 cmꢂ1. 1H NMR:
d 3.88 (3H, s), 7.39–7.49 (2H, m), 7.67–7.75 (1H,
m), 8.84 (1H, dd, J¼1.6, 7.9 Hz), 8.91–8.97 (2H, m,). 13C NMR:
d 30.7
(q), 115.0 (d), 119.3 (s), 119.6 (s), 123.5 (d), 125.8 (d), 132.6 (d), 136.8
(s), 139.3 (s), 145.5 (d), 148.3 (d), 160.7 (s). Anal. Calcd for C12H9N3O
(211.22): C, 68.24; H, 4.29; N,19.89. Found: C, 68.40; H, 4.38; N,19.83.
4.5.13. 5,7-Dimethyl-5H,6H,7H-pyrido[2,3-d][1]benzazepin-6-
one (25)
White solid, mp 162–164 ꢀC; yield 90%. IR (Nujol): 1632 cmꢂ1. 1H
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d
1.70 (3H, d, J¼6.7 Hz), 3.37 (3H, s), 3.60 (1H, q, J¼6.7 Hz),
´
´
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7.33–7.37 (2H, m), 7.41 (1H, d, J¼8.0 Hz), 7.49–7.56 (2H, m), 7.88
(1H, d, J¼7.6 Hz), 8.68 (1H, d, J¼4.7 Hz). 13C NMR:
d 11.7 (q), 36.7 (d),
43.2 (q), 122.6 (d), 123.0 (d), 125.7 (d), 129.6 (d), 130.1 (d), 132.0 (s),
132.1 (s),135.8 (d),142.0 (s),149.5 (d),156.1 (s), 172.4 (s). Anal. Calcd
for C15H14N2O (238.29): C, 75.61; H, 5.92; N, 11.76. Found: C, 75.54;
H, 5.81; N, 11.60.
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581–590.
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M. X.-C.; Mooney, M.; Morgan, L.; Qian, Y.; Tran, S.; Williams, L. R.; Wu, Q. Y.;
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References and notes
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