Novel annulated products from aminonaphthyridinones

Article abstract of DOI:10.1016/j.tet.2005.12.003

2-(4-Methoxyphenyl)-1-oxo-1,2-dihydro-1,6-naphthyridine-4-carboxamide (4c) underwent Hofmann rearrangement with iodobenzene diacetate in methanol to give the corresponding 4-amino compound (6c). This, when reacted with 2,4-pentanedione and then hot phosph

Full text of DOI:10.1016/j.tet.2005.12.003

Tetrahedron 62 (2006) 2313–2320
Novel annulated products from aminonaphthyridinones
*
Leslie W. Deady and Shane M. Devine
Chemistry Department, La Trobe University, Vic. 3086, Australia
Received 26 September 2005; revised 8 November 2005; accepted 1 December 2005
Available online 20 December 2005
Abstract—2-(4-Methoxyphenyl)-1-oxo-1,2-dihydro-1,6-naphthyridine-4-carboxamide (4c) underwent Hofmann rearrangement with
iodobenzene diacetate in methanol to give the corresponding 4-amino compound (6c). This, when reacted with 2,4-pentanedione and
then hot phosphoryl chloride (attempted Combes synthesis) gave a new heterocyclic system, 6-(4-methoxyphenyl)-2-methylpyrido[3,2-
c]pyrrolo[2,3-e]azocin-7(6H)-one (9c). This showed typical pyrrole-type reactivity at the 3-position. Alternatively, an attempt to convert the
4-NH2 in 6c to 4-OH by diazotization gave, instead, a [1,2,3]triazolo[1,5-a]pyridine-3-carboxaldehyde (16c). The same series of reactions on
a benzo analog, 2-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyridine-4-carboxamide (4a), gave the same results.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
We have previously demonstrated a useful transformation in
which tricyclic dione 2a, readily prepared by reaction of
Vilsmeier reagent on the quinoline derivative 1a, are
converted to acids 3 by reaction with a range of primary
amines (Scheme 1), and carboxamides derived from the
tricyclic series have revealed potent antitumor activity.1 As
part of a continuing search for new heterocyclic systems as
precursors of pharmacologically active derivatives, we
sought to convert the carboxyl group in 3 (now extended
to bicyclic, pyridine-based analogs) to amino and then build
a further ring by any of various well known methods. This
paper reports on success with the former and some
unexpected findings during the latter.
2. Results and discussion
2.1. Preparation of the amino compounds
Classical methods for the change –CO2H/–NH2 include
the Hofmann2a,3 and Curtius4 rearrangements. We have
concentrated on the former, and the necessary amide
intermediates 4 were prepared by standard conversion to
Scheme 1. (i) DMF–POCl3/0 8C, then 20 8C/2 h; (ii) DMFC2.5 mol
MeNH2–THF for a, b; 3 mol anisidineC4 mol NEt3 for c. All: 20 8C/16 h.
the acyl chloride followed by reaction with ammonia
(Scheme 2). Many variations on the original bromine/
aqueous sodium hydroxide rearrangement conditions have
been reported. Of particular interest was a method which
used iodobenzene diacetate in methanol under mild
conditions.5 In the present research, this worked well to
give methyl carbamates 5, which were hydrolyzed in alkali
to liberate the amines 6; the procedure was optimized so that
it was not necessary to isolate the carbamates.
Keywords: Hofmann rearrangement; Novel; Combes product;
Diazotization.
An interesting observation was that, for no obvious reason, the
stability of 6 was quite variable. Amine 6b was quite unstable;
*
Corresponding author. Tel.: C61 3 9479 2561;
e-mail: l.deady@latrobe.edu.au
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.12.003

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L. W. Deady, S. M. Devine / Tetrahedron 62 (2006) 2313–2320
intermediate7b (Scheme 3), and these general pathways are
applicable to many other aromatic amines.
The Conrad–Limpach synthesis with ethyl acetoacetate
proceeded as expected. By the standard route, a six-
membered ring was added to the bicyclic 6c and tricyclic
6a to give 7c and 7a, respectively (Scheme 4).
The first step of the Combes synthesis, condensation with
2,4-pentanedione, gave the isolable intermediates 8,
sufficiently pure for direct further use. However, treatment
with concentrated sulfuric acid or polyphosphoric acid at
100 8C failed to produce the desired cyclized product. The
products were neither purified nor identified, but it was clear
1
from H NMR analysis that the sidechains had been lost.
Scheme 2. (i) SOCl2/reflux 0.5 h. Evap, add CH2Cl2. Bubble NH3(g); (ii)
1.1 mol PhI(OAc)2/5 mol KOH/MeOH/5 8C, then 20 8C/0.5 h; (iii) Add
10 mol KOH/H2O/reflux 3 h.
At this point, we noted a literature report where sulfuric acid
produced ‘unsatisfactory results’ but where hot phosphoryl
chloride gave the desired product.8 When applied to 8c, a
substantial amount of a fawn solid was isolated, but early
NMR analysis showed this was not the expected product
(see Scheme 3); while the carbon count was the same as in
8c, there was only one methyl signal, and there were three
single proton signals in the region 5.9–6.3 ppm, not
expected for a fully aromatic product. Elemental analysis
was in accord with a formula equivalent to a loss of water
from 8c (giving a yield of 77%), and the novel structure 9c
was assigned from analysis of data from various NMR
experiments. Particularly informative were data for these
this compound had been previously reported by a different,
longer sequence and noted to be unstable.6 Some other
examples not covered in the present paper were also unstable
but, on the other hand, 6a (same NR group as 6b) and 6c (same
bicyclic system but different R group) were stable solids.
2.2. Attempted Combes synthesis
The construction of a further ring onto aniline is the basis of
many classic syntheses of quinoline derivatives. In particular,
b-keto esters (or ethoxymethylenemalonates) lead to
quinolin-4-ones (Conrad–Limpach synthesis).7a The closely
related Combes synthesis uses b-diketones as the 3-carbon
source and acidic conditions for cyclization of the
1
three protons showing in the alkene region of the H NMR
spectrum, now assigned as H-3 (d 5.85, s), H-4 (d 6.27, d,
JZ8.1 Hz), and H-5 (d 6.13, d, JZ8.1 Hz). 3JCH couplings
were crucial; from H–Me to C-3, from H-5 to the low field
C-7 (these fixed both ends of the 6 carbon sequence C–Me–
C-5), from both H-3 and H-4 to the same quaternary carbon,
C-11b. The absence of coupling between H-3 and H-4 was
consistent with the intermediacy of the quaternary carbon,
3
C-3a, which did show JCH coupling to H-1 and H-5. The
mechanism of this overall dehydration reaction, and the
reason why the conventional six-membered annulation did
not occur, is unclear. The enol form of the side chain,
probably as a phosphorus-containing derivative, is a likely
initiator of a sequence of ring forming and ring opening
steps to create the five- and eight-membered rings.
Scheme 3.
Scheme 4. (i) AcCH2CO2Et/CaSO4/HOAc/EtOH/reflux 3.5 h; (ii) Ph2O/250 8C/15 min; (iii) acac/CaSO4/HOAc/EtOH/reflux 3.5 h, (iv) POCl3/reflux 1 h;
(v) Br2/CH2Cl2/20 8C/10 min; (vi) 35 equiv POCl3–DMF/DMF/0 8C/1 h; (vii) Me2NHC2 ClK/(CH2O)n/EtOH/50 8C/4 h; (viii) MeI/C6H6–25%NaOH/TBAHS/
stir vigorously 20 8C/24 h.

L. W. Deady, S. M. Devine / Tetrahedron 62 (2006) 2313–2320
2315
The tetracyclic analogue 9a (64%) was formed in the same
way from 6a.
consistent with the presence of the N^N group.11 When
this salt was suspended in water and treated with 10%
sodium hydroxide, a white solid resulted, which was not the
target hydroxy compound but, rather, the triazolopyrido
aldehyde 16c. The formation of the triazole ring was
indirectly suggested by a characteristic change in chemical
shifts (proton and carbon) and coupling constants (proton)
of the A ring atoms compared with 6c and 14c. Cleavage of
the B ring was clear from characteristic NMR aldehyde
signals [d 10.22 (1H), 183.3 (13C) ppm], while assignment of
the singlet at d 10.48 ppm as the NH proton was based on its
exchange with D2O and 3JCH coupling with ortho protons in
the R group (–C6H4–OMe-p) in the HMBC spectrum.
The ready availability of this new system prompted some
further chemistry to check out the potential reactivity of the
azocine and/or pyrrole rings. It appears that the 4,5-double
bond in the former is reasonably stable while the latter
readily undergoes typical pyrrole reactions at the available
1- and 3-positions (the work was confined to the more
accessible 9c). Thus, bromination with bromine in chloro-
form was immediate to give 10c (92%), Vilsmeier reaction
gave the aldehyde 11c (83%), the Mannich reaction with
dimethylamine hydrochloride and paraformaldehyde gave a
64% yield of 12c, while reaction with methyl iodide under
phase transfer conditions, as for indole,9 gave the
anticipated N-methyl product 13c (88%). The ability to
readily attach reactive functionalities to the 3-position
potentially opens the way to further derivatization, and
hence to interesting compounds for pharmacological
testing.
While the triazolopyridine system is not new, this method of
formation is novel. The best standard synthesis appears to
be by heating the tosylhydrazone of a pyridine-2-carbox-
aldehyde in morpholine at 95–100 8C.12 A plausible
mechanism in the present case requires that, reasonably,
position 7 in 14c is more electron deficient than position 8
and hydrolysis occurs here as shown in Scheme 5. In this
case, the presumed intermediate 15c was not isolated. There
is precedence for water attack at an alternative highly
electron deficient centre in a diazonium derivative of a
quinolizinium ion.13 It is noteworthy that in the sequence of
Scheme 5, in contrast to the formation of compounds 9
earlier, cleavage of the naphthyridinone ring occurs at the
N-6–C-7 bond.
2.3. Diazotization of the amines
A second, quite different type of reaction on the amino
compounds 6a, 6c also led to unexpected annulation
products (Scheme 5).
While the same final result was obtained from the tricyclic
14a, some interesting differences emerged. For solubility
reasons, the diazotization reaction had to be carried out at
room temperature. A pink solid separated immediately but,
in this case, it was not the diazonium salt. The NMR
resolution was improved following precipitation of a white
solid by water addition to an acetonitrile solution. For this
compound, the 1H NMR spectrum was able to be obtained in
DMSO and contained, in addition to the expected aromatic
proton signals, two doublets at d 6.35 and 7.11 ppm (JZ
9.5 Hz). The latter disappeared on addition of D2O while the
former became a singlet. This compound was therefore
assigned structure 15a, the proposed immediate hydrolysis
product of the diazonium salt, and apparently more stable in
the tricyclic than bicyclic case. Rapid isomerization to the
ring-open aldehyde 16a was brought about by treatment
with 1% aqueous NaOH. In this case where RZMe, the
methyl signal in the NMR spectrum occurred as a doublet
(JZ4.4 Hz), providing further evidence for the ring
cleavage having resulted in formation of the NH group.
Interestingly, the above DMSO/D2O NMR sample of 15a
quite rapidly changed to a mixture of 15a and 16a.
Scheme 5. (i) NaNO2/43% HBF4/H2O/0 8C/1 h; (ii) NaNO2/43% HBF4/
H2O/20 8C/1 h, then MeCN/H2O/5 min; (iii) 1% NaOH/20 8C/1 h; (iv)
5 mol Na2S2O5/H2O/reflux 4 h, then 10 mol NaOH/reflux 24 h.
The aim was to convert the amino to a hydroxy function, to
prepare analogues of 8-hydroxyquinoline. A traditional way
of achieving this conversion for aromatic amines is by
hydrolysis of an intermediate diazonium salt.2b When 6c in
fluoroboric acid at 0 8C was treated with aqueous sodium
nitrite,10 a solid was precipitated. This was unstable in most
solvents, for example, DMSO (immediate bubbling) but a
1H NMR spectrum was obtained in acetone. Its general form
suggested that the bicyclic system was intact and the
compound was most likely the anticipated diazonium salt
2.4. Corollary
The synthesis of the hydroxy compound 17c has been
achieved by reaction of 6c with aqueous bisulfite, the
Bucherer reaction14 (Scheme 5). This was interesting as the
Bucherer reaction is of limited scope and is typically applied
to naphthalene derivatives. However, the yield of 17c was
unaccountably variable, while low yields of unidentified
products resulted when the same conditions were applied to
some analogs of 6c.
14c. The IR spectrum contained a strong band at 2228 cmK1
,

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L. W. Deady, S. M. Devine / Tetrahedron 62 (2006) 2313–2320
3. Experimental
for 4a, and obtained as a white solid (89%), mp 276–278 8C
(from 1,4-dioxane). H NMR (DMSO-d6): d 3.59 (s, 3H,
1
N–CH3), 7.59 (dd, JZ8.1, 4.5 Hz, 1H, H-3), 7.68 (br s, 1H,
NH), 8.57 (s, 1H, H-7), 8.62 (dd, JZ8.1, 1.8 Hz, 1H, H-4),
8.98 (dd, JZ4.5, 1.8 Hz, 1H, H-2), 9.71 (br s, 1H, NH). 13C
NMR (DMSO-d6), 100 8C: d 36.7 (N–CH3), 109.2 (C-8),
120.5 (C-4a), 121.9 (C-3), 136.9 (C-4), 143.8 (C-7), 150.7
(C-8a), 153.2 (C-2), 161.7 (C-5), 164.7 (CONH2). Anal.
Calcd for C10H9N3O2: C, 59.11; H, 4.46; N, 20.68. Found:
C, 59.11; H, 4.62; N, 20.76%.
3.1. General
NMR spectra were recorded at 300.13 MHz (1H) and
75.47 MHz (13C) on a Bruker Avance 300 spectrometer.
Chemical shifts are reported as d values (ppm) relative to
Me4Si. Standard PENDANT, HSQC, and HMBC spectra
were used in making the NMR assignments. Melting points
are uncorrected. Microanalyses were performed at the
Campbell Microanalytical Laboratory, University of
Otago, New Zealand.
3.3.3. 6-(4-Methoxyphenyl)-5-oxo-5,6-dihydro-1,6-
naphthyridine-8-carboxamide (4c). This was prepared
from acid 3c, as for 4a, and obtained as white needles
(98%), mp 285–286 8C (from 1,4-dioxane). 1H NMR
(DMSO-d6): d 3.80 (s, 3H, O–CH3), 7.06 (d, JZ8.6 Hz,
2H, H-30, H-50), 7.43 (d, JZ8.6 Hz, 2H, H-20, H-60), 7.65
(dd, JZ8.0, 4.6 Hz, 1H, H-3), 7.79 (br s, 1H, NH), 8.31 (s,
1H, H-7), 8.65 (d, JZ8.0 Hz, 1H, H-4), 9.03 (d, JZ4.6 Hz,
1H, H-2), 9.73 (br s, 1H, NH). 13C NMR (DMSO-d6): d 55.6
(O–CH3), 109.1 (C-8), 114.5 (C-30, C-50), 121.2 (C-4a),
122.5 (C-3), 128.2 (C-20, C-60), 133.1 (C-10), 137.6 (C-4),
143.2 (C-7), 150.6 (C-8a), 153.7 (C-2), 159.3 (C-40), 161.5
(C-5), 164.5 (CONH2). Anal. Calcd for C16H13N3O3: C,
65.08; H, 4.44; N, 14.23. Found: C, 64.84; H, 4.49; N,
14.20%.
3.2. Precursors
Diones 21a,15 and acid 3a1a were prepared as previously
reported. Acid 3b, earlier synthesized from the dione by
reaction with hot POCl3,15 was better prepared by reaction
with methylamine,16 as for 3a.
3.2.1. 6-(4-Methoxyphenyl)-5-oxo-5,6-dihydro-1,6-naph-
thyridine-8-carboxylic acid (3c). To a suspension of dione
2b,c (2.26 g, 10.37 mmol) in DMF (34 mL) was added Et3N
(5.65 mL) followed by p-anisidine (3.83 g, 31.10 mmol),
and the whole was stirred for 16 h. Ice/water (ca. 100 mL)
was added and the mixture was taken to pH 1 with 3.3%
HCl. The resultant precipitate was filtered and washed with
water to give carboxylic acid 3c (1.86 g, 61%) as a beige
solid, mp 245–246 8C, which was used without further
3.4. Hofmann rearrangement
1
purification. H NMR (DMSO-d6): d 3.80 (s, 3H, O–CH3),
3.4.1. 4-Amino-2-methylbenzo[b][1,6]naphthyridin-
1(2H)-one (6a). A solution of KOH (1.11 g, 19.78 mmol)
in MeOH (10 mL) was cooled to approximately 5 8C. To
this mixture was added iodobenzene diacetate (1.40 g,
4.35 mmol) and carboxamide 4a (1.00 g, 3.95 mmol). The
mixture was allowed to warm to room temperature and was
then stirred vigorously for 30 min to make the intermediate
carbamate 5a. A solution of KOH (2.22 g, 39.57 mmol) in
MeOH (10 mL) and water (2 mL) was added, and the whole
was heated under reflux for 3 h. The dark red solution was
cooled, and the solid, which separated was collected by
filtration and washed with water to give amine 6a as orange
needles (0.54 g, 61%), mp 197–199 8C (dec) (from EtOH).
Extraction of the filtrate with CH2Cl2 (2!20 mL) gave a
further 0.08 g. 1H NMR (DMSO-d6): d 3.44 (s, 3H, N–CH3),
4.76 (br s, 2H, NH2), 6.96 (s, 1H, H-3), 7.63 (t, JZ7.4 Hz,
1H, H-8), 7.91 (t, JZ7.7 Hz, 1H, H-7), 8.10 (d, JZ8.6 Hz,
1H, H-6), 8.25 (d, JZ8.4 Hz, 1H, H-9), 9.27 (s, 1H, H-10).
13C NMR (DMSO-d6): d 35.8 (N–CH3), 116.4 (C-3), 120.0
(C-10a), 126.0 (C-4), 126.3 (C-9a), 126.4 (C-8), 128.4
(C-6), 129.8 (C-9), 132.5 (C-7), 138.3 (C-10), 146.7 (C-4a),
149.1 (C-5a), 159.1 (C-1). Anal. Calcd for C13H11N3O: C,
69.32; H, 4.92; N, 18.65. Found: C, 69.04; H, 5.12; N,
18.48%.
7.07 (d, JZ8.9 Hz, 2H, H-30, H-50), 7.44 (d, JZ8.9 Hz, 2H,
H-20, H-60), 7.76 (dd, JZ8.1, 4.8 Hz, 1H, H-3), 8.35 (s, 1H,
H-7), 8.74 (dd, JZ8.1, 1.4 Hz, 1H, H-4), 9.07 (dd, JZ4.8,
1.4 Hz, 1H, H-2), 15.18 (br s, 1H, CO2H). 13C NMR
(DMSO-d6): d 55.6 (O–CH3), 104.6 (C-8), 114.5 (C-30,
C-50), 121.1 (C-4a), 123.3 (C-3), 128.2 (C-20, C-60), 132.7
(C-10), 1380.8 (C-4), 145.2 (C-7), 150.2 (C-8a), 152.6 (C-2),
159.4 (C-4 ), 161.1 (C-5), 164.8 (CO2H).
3.3. Preparation of amides
3.3.1. 2-Methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naph-
thyridine-4-carboxamide (4a). Acid 3a (2.41 g,
9.49 mmol) in SOCl2 (24 mL) was heated under reflux for
30 min. The excess SOCl2 was removed in vacuo and
CH2Cl2 (40 mL) was added to the residue. Ammonia
gas was bubbled through the mixture for 5 min, which
was then evaporated at reduced pressure. Water was added
and the mixture was filtered to give 4a as a pale yellow solid
1
(2.31 g, 96%), mp O300 8C (from 1,4-dioxane). H NMR
(DMSO-d6): d 3.60 (s, 3H, N–CH3), 7.66 (t, JZ7.4 Hz, 1H,
H-8), 7.77 (br s, 1H, NH), 7.94 (t, JZ7.7 Hz, 1H, H-7), 8.16
(d, JZ8.6 Hz, 1H, H-6), 8.27 (d, JZ8.3 Hz, 1H, H-9), 8.62
(s, 1H, H-3), 9.37 (s, 1H, H-10), 10.09 (br s, 1H, NH). 13C
NMR (DMSO-d6), 100 8C: d 36.5 (N–CH3), 109.1 (C-10a),
119.5 (C-4), 125.7 (C-9a), 126.8 (C-8), 128.1 (C-6), 129.6
(C-9), 133.2 (C-7), 139.3 (C-10), 144.9 (C-3), 148.7 (C-5a),
149.8 (C-4a), 162.2 (C-1), 164.9 (CONH2). Anal. Calcd for
C14H11N3O2$0.1H2O: C, 65.93; H, 4.43; N, 16.47. Found:
C, 65.82; H, 4.51; N, 16.30%.
3.4.2. 8-Amino-6-methyl-1,6-naphthyridin-5(6H)-one
(6b). This was prepared from 4b, as for 6a. Water was
added to the red reaction solution, which was then
neutralized with AcOH and evaporated to dryness at
reduced pressure. The residue was boiled with chloroform
and filtered. Evaporation of the chloroform from the filtrate
gave amine 6b as a brown solid (86%), which was unstable
1
3.3.2. 6-Methyl-5-oxo-5,6-dihydro-1,6-naphthyridine-8-
carboxamide (4b). This was prepared from acid 3b, as
and rapidly decomposed. H NMR (DMSO-d6): d 3.42 (s,
3H, N–CH3), 4.68 (br s, 2H, NH2), 6.93 (s, 1H, H-7), 7.52

L. W. Deady, S. M. Devine / Tetrahedron 62 (2006) 2313–2320
2317
(dd, JZ8.0, 4.5 Hz, 1H, H-3), 8.51 (dd, JZ8.0, 1.7 Hz, 1H,
H-4), 8.90 (dd, JZ4.5, 1.7 Hz, 1H, H-2). 13C NMR
(DMSO-d6): d 36.1 (CH3), 116.2 (C-7), 120.9 (C-4a),
122.1 (C-3), 126.3 (C-8), 136.0 (C-4), 147.0 (C-8a), 153.1
(C-2), 158.5 (C-5).
125.4 (C-8), 126.6 (C-10b), 128.2 (C-4a), 128.6 (C-20,
C-60), 133.4 (C-10), 137.0 (C-7), 145.2 (C-10a), 146.1 (C-2),
154.2 (C-9), 157.9 (C-40), 160.2 (C-6), 169.5 (C-4). Anal.
Calcd for C19H15N3O3: C, 68.46; H, 4.54; N, 12.61. Found:
C, 68.04; H, 4.66; N, 12.79%.
3.4.3. 8-Amino-6-(4-methoxyphenyl)-1,6-naphthyridin-
5(6H)-one (6c). This was prepared from 4c, as for 6a, and
obtained as yellow needles (68%), mp 164–165 8C (from
EtOH). 1H NMR (DMSO-d6): d 3.78 (s, 3H, O–CH3), 4.72
(br s, 2H, NH2), 6.91 (s, 1H, H-7), 7.02 (d, JZ8.8 Hz, 2H,
H-30, H-50), 7.35 (d, JZ8.8 Hz, 2H, H-20, H-60), 7.58 (dd,
JZ8.0, 4.5 Hz, 1H, H-3), 8.55 (d, JZ8.0 Hz, 1H, H-4), 8.96
(d, JZ4.5 Hz, 1H, H-2). 13C NMR (DMSO-d6): d 55.5
(O–CH3), 114.3 (C-30, C-50), 115.9 (C-7), 121.5 (C-4a),
122.5 (C-3), 126.6 (C-8), 128.0 (C-20, C-60), 134.3 (C-10),
136.5 (C-4), 147.4 (C-8a), 153.5 (C-2), 158.4 (C-40), 158.5
(C-5). Anal. Calcd for C15H13N3O2: C, 67.41; H, 4.90; N,
15.72. Found: C, 67.10; H, 5.07; N, 15.45%.
3.6. Attempted Combes synthesis
3.6.1. 4-[2-Methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naph-
thyridin-4-yl]aminopent-3-en-2-one (8a). To a solution of
6a (0.25 g, 1.11 mmol) in EtOH (25 mL), was added
2,4-pentanedione (0.14 g, 1.44 mmol), CaSO4 (0.76 g,
5.56 mmol) and AcOH (2.5 mL). The red mixture was
heated under reflux for 3.5 h, then filtered and the filtrate
was evaporated under reduced pressure to give 8a as a
red solid (0.33 g, 97%), used in this state in the next
reaction. 1H NMR (DMSO-d6): d 1.98 (s, 3H, CH3-5), 2.01
(s, 3H, CH3-1), 3.52 (s, 3H, N–CH3), 5.28 (s, 1H, H-3), 7.65
(t, JZ7.5 Hz, 1H, H-80), 7.87 (s, 1H, H-30), 7.91 (t, JZ
7.7 Hz, 1H, H-70), 8.04 (d, JZ8.6 Hz, 1H, H-60), 8.27 (d,
JZ8.3 Hz, 1H, H-90), 9.31 (s, 1H, H-100), 12.25 (s, 1H,
NH). 13C NMR (DMSO-d6): d 19.6 (CH3-5), 29.1 (CH3-1),
36.2 (N–CH3), 97.6 (C-3), 116.6 (C), 119.6 (C), 126.3
(C-9a0), 126.7 (C-80), 128.6 (C-60), 129.8 (C-900), 132.9
(C-70)0, 133.3 (C-300), 138.5 (C-100), 148.4 (C-4a ), 149.5
(C-5a ), 160.9 (C-1 ), 161.2 (C-4), 194.7 (C-2).
3.5. Conrad–Limpach synthesis
3.5.1. 2,5-Dimethylquinolino[3,2-c][1,6]naphthyridine-
4,6(1H,5H)-dione (7a). To a warm solution of amine 6a
(0.34 g, 1.51 mmol) in EtOH (35 mL) was added ethyl
acetoacetate (0.26 g, 1.96 mmol), CaSO4 (1.03 g,
7.56 mmol) and AcOH (3.5 mL). This mixture was heated
under reflux for 3.5 h, then filtered while hot and the filtrate
was evaporated under reduced pressure to give the crotonate
intermediate as an orange solid (0.46 g, 90%). A sample
(0.26 g, 0.77 mmol) was added in portions to Ph2O (2 mL)
heated at 250 8C, and the solution was heated for a further
15 min. After being cooling to room temperature, the
solution was poured onto Et2O (50 mL) and the resultant
precipitate was filtered and washed thoroughly with hot
Et2O to give 7a as a brown solid (0.20 g, 89%), mp
159–162 8C [from CH2Cl2/petroleum spirit (bp
80–110 8C)]. 1H NMR (DMSO-d6): d 2.43 (s, 3H,
C–CH3), 4.01 (s, 3H, N–CH3), 6.17 (s, 1H, H-3), 7.76
(t, JZ7.5 Hz, 1H, H-9), 8.03 (t, JZ7.8 Hz, 1H, H-10), 8.30
(d, JZ8.7 Hz, 1H, H-11), 8.36 (d, JZ8.4 Hz, 1H, H-8), 9.40
(s, 1H, H-7), 11.61 (br s, 1H, NH). 13C NMR (DMSO-d6): d
18.7 (C–CH3), 33.2 (N–CH3), 116.1 (C-3), 119.7 (C), 126.8
(C), 127.6 (C-7a), 127.7 (C-9), 128.4 (C-4a, C-11), 129.9
(C-8), 133.3 (C-10), 138.9 (C-7), 143.7 (C-12a), 146.1
(C-2), 149.0 (C-11a), 160.4 (C-6), 171.7 (C-4). Anal. Calcd
for C17H13N3O2$0.5H2O: C, 67.99; H, 4.70; N, 13.99.
Found: C, 68.08; H, 4.73; N, 13.60%.
3.6.2. 8-[6-(4-Methoxyphenyl)-5-oxo-5,6-dihydro-1,6-
naphthyridin-8-yl]aminopent-3-en-2-one (8c). This was
prepared from 6c, as for 8a, and obtained as a red solid
1
(87%), used in this state in the next reaction. H NMR
(DMSO-d6): d 1.95 (s, 3H, CH3-5), 1.96 (s, 3H, CH3-1),
3.79 (s, 3H, O–CH3), 5.22 (s, 1H, H-3), 7.02 (d, JZ8.8 Hz,
2H, H-300, H-500), 7.35 (d, JZ8.8 Hz, 2H, H-200, H-600), 7.58
(dd, JZ8.0, 4.5 Hz, 1H, H-30), 7.75 (s, 1H, H-70), 8.55 (d,
JZ8.0 Hz, 1H, H-40), 8.99 (dd, JZ4.5 Hz, 1H, H-20). 13C
NMR (DMSO-d6): d 19.4 (C-5), 29.1 (C-1), 55.6 (O–CH3),
97.6 (C-3), 114.3 (C-300,00C-500), 117.2 (C-80), 121.4 (C-4a0),
123.0 (C-30), 128.3 (C-2 , C-600), 132.4 (C-070), 133.3 (C-100),
136.5 (C-40), 149.6 (C-8a0), 154.6 (C-2 ), 158.9 (C-400),
160.2 (C-50), 161.3 (C-4) 194.8 (C-2).
3.6.3. 2,6-Dimethylpyrrolo[20,30:5,6]azocino[4,3-b]-
quinolin-7(6H)-one (9a). Compound 8a (0.33 g,
1.07 mmol) was added to POCl3 (10 mL) and the whole
was heated under reflux for 1 h. The solvent was evaporated
under reduced pressure and water (30 mL) was added. The
brown mixture was filtered, and the filtrate was basified with
10% NaOH. The solid, which separated was filtered and
washed with water to give 9a (0.20 g, 64%) as a light brown
solid. For microanalysis, a sample on a short bed of silica
was eluted with EtOAc–hexane (1/1). The residue after
evaporation of the solvents was recrystallized from MeCN
to give 9a as a mustard solid, mp 294–296 8C (after
3.5.2. 5-(4-Methoxyphenyl)-2-methylpyrido[3,2-h]-
[1,6]naphthyridine-4,6(1H,5H)-dione (7c). This was pre-
pared from amine 6c, as for 7a, and obtained as a light
brown solid (71%). For microanalysis, a sample on a short
bed of silica was washed with EtOAc, then eluted with
MeCN. The residue after evaporation of the MeCN was
recrystallized from MeCN to give 7c as a fawn solid, mp
1
darkening O270 8C). H NMR (DMSO-d6): d 2.25 (s, 3H,
C–CH3), 3.00 (s, 3H, N–CH3), 5.78 (d, JZ2.0 Hz, 1H, H-3),
6.12 (d, JZ8.3 Hz, 1H, H-4), 6.16 (d, JZ8.3 Hz, 1H, H-5),
7.53 (t, JZ7.5 Hz, 1H, H-10), 7.75 (t, JZ7.7 Hz, 1H,
H-11), 7.91–7.98 (m, 2H, H-9, H-12), 8.32 (s, 1H, H-8),
11.57 (br s, 1H, NH). 13C NMR (DMSO-d6): d 12.7
(C–CH3), 35.4 (N–CH3), 106.9 (C-3), 119.2 (C-3a), 120.5
(C-4), 125.7 (C-8a), 126.3 (C-10), 128.2 (C-12), 128.3
(C-9), 128.6 (C-5), 128.9 (C-13b), 130.8 (C-11), 132.0
1
298–300 8C. H NMR (DMSO-d6): d 2.35 (s, 3H, C–CH3),
3.76 (s, 3H, O–CH3), 5.92 (s, 1H, H-3), 6.85 (d, JZ8.9 Hz,
2H, H-30, H-50), 7.05 (d, JZ8.9 Hz, 2H, H-20, H-60), 7.81
(dd, JZ8.0, 4.5 Hz, 1H, H-8), 8.62 (dd, JZ8.0, 1.7 Hz, 1H,
H-7), 9.14 (dd, JZ4.5, 1.7 Hz, 1H, H-9), 11.80 (br s, 1H,
NH). 13C NMR (DMSO-d6): d 18.6 (C–CH3), 55.3
(O–CH3), 112.9 (C-30, C-50), 115.5 (C-3), 122.4 (C-6a),

2318
L. W. Deady, S. M. Devine / Tetrahedron 62 (2006) 2313–2320
(C-2), 132.2 (C-7a), 136.1 (C-8), 147.3 (C-12a), 148.8
(C-13a), 167.3 (C-7). Anal. Calcd for C18H15N3O: C, 74.72;
H, 5.23; N, 14.52. Found: C, 74.50; H, 5.29; N, 14.60%.
1.5 Hz, 1H, H-10), 9.91 (s, 1H, CHO), 12.40 (br s, 1H, NH).
13C NMR (DMSO-d6): d 11.2 (C–CH3), 55.4 (O–CH3),
114.2 (C-30, C-50), 117.6 (C-3a), 119.6 (C-3), 121.8 (C-4),
122.4 (C-9), 127.6 (C-20, C-60), 128.9 (C-5), 130.2 (C-11b),
132.9 (C-10), 133.8 (C-7a), 136.4 (C0-8), 142.0 (C-2), 145.6
(C-11a), 150.0 (C-10), 158.1 (C-4 ), 167.0 (C-7), 185.1
(CHO). Anal. Calcd for C21H17N3O3: C, 70.18; H, 4.77; N,
11.69. Found: C, 70.59; H, 4.89; N, 11.67%.
3.6.4. 6-(4-Methoxyphenyl)-2-methylpyrido[3,2-c]-
pyrrolo[2,3-e]azocin-7(6H)-one (9c). This was prepared
from 8c, as for 9a, and 9c (77%) was purified in the same
way (elution with acetone) and obtained as a fawn solid, mp
1
244–246 8C after recrystallization from toluene. H NMR
(DMSO-d6): d 2.24 (s, 3H, C–CH3), 3.73 (s, 3H, O–CH3),
5.85 (s, 1H, H-3), 6.13 (d, JZ8.1 Hz, 1H, H-5), 6.27 0(d, JZ
8.1 Hz, 1H, H-4), 6.940(d, JZ8.7 Hz, 2H, H-30, H-5 ), 7.16
(d, JZ8.7 Hz, 2H, H-2 , H-60), 7.32 (dd, JZ7.7, 4.4 Hz, 1H,
H-9), 7.91 (d, JZ7.7 Hz, 1H, H-8), 8.59 (d, JZ4.4 Hz, 1H,
H-10), 11.46 (br s, 1H, NH). 13C NMR (DMSO-d6): d 12.7
(C–CH3), 55.4 (O–CH3), 106.4 (C-3), 114.2 (C-30, C-50),
118.5 (C-3a), 121.2 (C-9), 122.2 (C-4), 127.8 (C-20, C-60),
127.9 (C-5), 129.0 (C-11b), 130.3 (C-2), 133.1 (C-7a),
133.3 (C-10), 136.1 (C-8), 147.3 (C-11a), 149.6 (C-10),
158.1 (C-40), 167.5 (C-7). Anal. Calcd for C20H17N3O2: C,
72.49; H, 5.17; N, 12.68. Found: C, 72.57; H, 5.00; N,
12.71%.
3.9. Mannich reaction
3.9.1. 3-(Dimethylamino)methyl-6-(4-methoxyphenyl)-
2-methylpyrido[3,2-c]pyrrolo[2,3-e]azocin-7(6H)-one
(12c). To a mixture of dimethylamine hydrochloride
(0.96 g) and paraformaldehyde (0.48 g) in EtOH (15 mL)
was added azocine 9c (0.12 g, 0.36 mmol) and the whole
was heated at 50 8C for 4 h. The mixture was evaporated at
reduced pressure and water (30 mL) was added. The
solution was basified with 10% NaOH solution and
extracted with CH2Cl2 (3!10 mL). The combined extracts
were washed with water (2!20 mL), dried over MgSO4 and
evaporated under reduced pressure to give 12c (0.09 g,
64%) as a light brown solid, mp 112–114 8C (from toluene).
1H NMR (DMSO-d6): d 2.10 [s, 6H, N(CH3)2], 2.21 (s, 3H,
C–CH3), 3.17 (d, JZ4.9 Hz, 2H, CH2), 3.73 (s, 3H,
O–CH3), 6.14 (d, JZ8.2 Hz, 1H, H-5), 6.32 (d, JZ
8.2 Hz, 1H, H-4), 6.92 (d, JZ8.9 Hz, 2H, H-30, H-50),
7.23 (d, JZ8.9 Hz, 2H, H-20, H-60), 7.32 (dd, JZ7.8,
4.7 Hz, 1H, H-9), 7.90 (dd, JZ7.8, 1.5 Hz, 1H, H-8), 8.59
(dd, JZ4.7, 1.5 Hz, 1H, H-10), 11.39 (br s, 1H, NH). 13C
NMR (DMSO-d6): d 10.9 (C–CH3), 45.0 [N(CH3)2], 53.8
(CH2), 55.4 (O–CH3), 114.0 (C-30, C-50), 115.5 (C-3), 118.7
(C-3a), 121.1 (C-9), 122.1 (C-4), 127.8 (C-020, C-60, C-5),
128.1 (C-11b), 129.9 (C-2), 133.2 (C-7a, C-01 ), 136.0 (C-8),
147.4 (C-11a), 149.6 (C-10), 158.0 (C-4 ), 167.3 (C-7).
Anal. Calcd for C23H24N4O2$0.25H2O: C, 70.29; H, 6.28;
N, 14.26. Found: C, 70.32; H, 6.17; N, 14.11%.
3.7. Bromination
3.7.1. 3-Bromo-6-(4-methoxyphenyl)-2-methylpyrido-
[3,2-c]pyrrolo[2,3-e]azocin-7(6H)-one (10c). To a solution
of 9c (0.14 g, 0.42 mmol) in CH2Cl2 (30 mL) was added
bromine (0.11 g, 0.69 mmol). The solution was stirred for
10 min, washed with 10% K2CO3 (2!20 mL), and the
organic phase was dried with MgSO4 and evaporated to give
10c (0.16 g, 92%) as a fawn solid, mp 227–230 8C [from
CH2Cl2/petroleum spirit (bp 80–110 8C)]. 1H NMR
(DMSO-d6): d 2.22 (s, 3H, C–CH3), 3.73 (s, 3H, O–CH3),
6.13 (d, JZ8.0 Hz, 1H, H-40), 6.27 (d, JZ8.0 Hz, 1H, H-5),
6.97 (d, JZ8.9 Hz, 2H, H-3 , H-50), 7.15 (d, JZ8.9 Hz, 2H,
H-20, H-60), 7.40 (dd, JZ7.8, 4.8 Hz, 1H, H-9), 7.98 (dd,
JZ7.8, 1.6 Hz, 1H, H-8), 8.63 (dd, JZ4.8, 1.6 Hz, 1H, H-
10), 12.05 (br s, 1H, NH). 13C NMR (DMSO-d6): d 11.5 (C–
CH3), 55.5 (O–CH3), 94.8 (C-3), 114.3 (C-30, C-50), 117.7
(C-3a), 120.4 (C-4), 122.0 (C-9), 127.6 (C-20, 0C-60), 128.8
(C-11b), 129.5 (C-2), 129.7 (C-5), 132.8 (C-1 ), 133.4 (C-
7a), 136.5 (C-8), 146.4 (C-11a), 149.8 (C-10), 158.2 (C-40),
167.0 (C-7). Anal. Calcd for C20H16BrN3O2$0.5H2O: C,
57.29; H, 4.09; N, 10.02. Found: C, 57.70; H, 4.09; N,
10.00%.
3.10. N-Methylation
3.10.1. 1-Methyl-6-(4-methoxyphenyl)-2-methylpyrido-
[3,2-c]pyrrolo[2,3-e]azocin-7(6H)-one (13c). To a stirred
solution of azocine 9c (0.24 g, 0.73 mmol) in C6H6 (20 mL),
was added 25% NaOH solution (15 mL), tetra-n-butyl-
ammonium hydrogen sulfate (0.27 g, 0.80 mmol) and
methyl iodide (1 mL). The biphasic mixture was stirred
vigorously for 24 h. Water (20 mL) was added and the
organic phase was separated, washed with water (3!
20 mL), dried over MgSO4 and evaporated under reduced
pressure to give 13c as a brown solid (0.22 g, 88%), mp
157–160 8C [from petroleum spirit (bp 80–110 8C)]. 1H
NMR (DMSO-d6): d 2.25 (s, 3H, C–CH3), 3.60 (s, 3H,
N–CH3), 3.73 (s, 3H, O–CH3), 5.92 (s, 1H, H-3), 6.13
(d, JZ8.1 Hz, 1H, H-5), 6.26 (d, JZ8.1 Hz, 1H, H-4), 6.94
(d, JZ8.9 Hz, 2H, H-30, H-50), 7.17 (d, JZ8.9 Hz, 2H, H-20,
H-60), 7.36 (dd, JZ7.8, 4.8 Hz, 1H, H-9), 7.96 (dd, JZ7.8,
1.5 Hz, 1H, H-8), 8.65 (dd, JZ4.8, 1.5 Hz, 1H, H-10). 13C
NMR (DMSO-d6): d 12.0 (C–CH3), 31.7 (N–CH3), 55.4
(CH3, O–CH3), 106.0 (C-3), 114.2 (C-30, C-50), 118.3
(C-3a), 121.3 (C-9), 122.1 (C-4), 127.7 (C-20, C-60), 128.7
(C-5), 129.9 (C-11b), 132.9 (C-10), 133.4 (C-2), 134.7
(C-7a), 135.7 (C-8), 146.9 (C-11a), 149.4 (C-10), 158.1
3.8. Vilsmeier–Haack formylation
3.8.1. 3-Formyl-6-(4-methoxyphenyl)-2-methylpyrido-
[3,2-c]pyrrolo[2,3-e]azocin-7(6H)-one (11c). To DMF
(2 mL) at 0 8C was added POCl3 (1 mL), dropwise and
with stirring. Azocine 9c (0.10 g, 0.30 mmol) in DMF
(2 mL) was added. The cold solution was stirred for 1 h,
then poured onto ice/water (30 mL) and basified to pH 9
with 10% NaOH solution. The resultant brown precipitate
was filtered and washed with water to give aldehyde 11c
(0.09 g, 83%) as a brown solid, mp 257–259 8C (from
toluene). 1H NMR (DMSO-d6): d 2.54 (s, 3H, C–CH3), 3.73
(s, 3H, O–CH3), 6.27 (d, JZ8.1 Hz, 1H, H-5), 6.51 (d, JZ
8.1 Hz, 1H, H-4), 6.940(d, JZ8.9 Hz, 2H, H-30, H-50), 7.17
(d, JZ8.9 Hz, 2H, H-2 , H-60), 7.45 (dd, JZ7.8, 4.8 Hz, 1H,
H-9), 8.01 (dd, JZ7.8, 1.5 Hz, 1H, H-8), 8.68 (dd, JZ4.8,

L. W. Deady, S. M. Devine / Tetrahedron 62 (2006) 2313–2320
2319
(C-40), 167.0 (C-7). Anal. Calcd for C21H19N3O2: C, 73.03;
H, 5.54; N, 12.17. Found: C, 72.95; H, 5.66; N, 12.12%.
stirred for 1 h. A white solid was filtered to give aldehyde
16a (0.16 g, 89%), mp 241–243 8C (after darkening
O205 8C) [from 1,4-dioxane–DMF (9/1)]. 1H NMR
(DMSO-d6): d 2.86 (d, JZ4.4 Hz, 3H, N–CH3), 7.83 (t,
JZ7.4 Hz, 1H, H-7), 8.01 (t, JZ7.8 Hz, 1H, H-8), 8.22 (d,
JZ8.0 Hz, 1H, H-6), 8.35 (s, 1H, H-5), 8.78 (d, 1H, JZ
8.3 Hz, H-9), 8.83 (br s, 1H, NH), 10.31 (s, 1H, CHO). 13C
NMR (DMSO-d6): d 26.4 (N–CH3), 116.1 (C-9), 123.0
(C-5a), 124.5 (C-4), 128.7 (C-7), 130.0 (C-6), 130.5 (C-3a),
130.8 (C-5), 130.9 (C-9a), 132.8 (C-8), 138.5 (C-3), 165.3
(CO), 184.2 (CHO). Anal. Calcd for C13H10N4O2: C, 61.41;
H, 3.96; N, 22.04. Found: C, 61.25; H, 4.16; N, 22.30%.
3.11. Diazotization
3.11.1. 6-(4-Methoxyphenyl)-5-oxo-5,6-dihydro-1,6-
naphthyridine-8-diazonium tetrafluoroborate (14c). To
a solution of amine 6c (0.20 g, 0.75 mmol) in 43% HBF4
(2 mL) at 0 8C was added, dropwise, NaNO2 (0.06 g,
0.90 mmol) in water (1 mL). The orange mixture was
stirred for 1 h at 0 8C. The yellow solid was filtered and
washed with Et2O to give 14c (0.20 g, 73%), mp
1
148–151 8C (dec). H NMR (acetone-d6): d 3.88 (s, 3H,
O–CH3), 7.13 (d, JZ8.9 Hz, 2H, H-30, H-50), 7.58 (d, JZ
8.9 Hz, 2H, H-20, H-60), 7.92 (dd, JZ8.0, 4.7 Hz, 1H, H-3),
8.76 (dd, JZ8.0, 1.0 Hz, 1H, H-4), 9.18 (dd, JZ4.7, 1.0 Hz,
1H, H-2), 9.97 (s, 1H, H-7). 13C NMR (acetone-d6): d 54.9
(O–CH3), 90.5 (C-8), 114.3 (C-30, C-50), 120.9 (C-4a),
125.4 (C-3), 127.7 (C-20, C-60), 130.8 (C-10), 137.5 (C-4),
143.9 (C-8a), 156.0 (C-2), 156.5 (C-7), 159.7 (C-5), 160.7
3.12. Bucherer reaction
3.12.1. 8-Hydroxy-6-(4-methoxyphenyl)-1,6-naphthyri-
din-5(6H)-one (17c). To a solution of sodium metabisulfite
(0.85 g, 4.49 mmol) in water (15 mL) was added amine 6c
(0.24 g, 0.90 mmol) and the yellow mixture was heated
under reflux for 24 h. After this time, the ensuing orange
solution was cooled to room temperature, whereby a yellow
solid separated. KOH (0.50 g, 8.99 mmol) was added and
the mixture was heated under reflux for 24 h. The solution
was then cooled until a yellow precipitate formed, which
was collected by filtration to give unreacted 6c (0.10 g). The
filtrate was neutralized with concentrated HCl and the green
solid, which separated was filtered and washed with water
(0.45 g). Recrystallization from MeCN gave 17c (0.11 g,
46%) as a yellow solid (which rapidly turned green), mp
174–175 8C. 1H NMR (DMSO-d6): d 3.79 (s, 3H, O–CH3),
7.02 (dd, JZ6.8, 2.2 Hz, 2H, H-300, H-500), 7.11 (s, 1H, H-7),
7.36 (dd, JZ6.8, 2.2 Hz, 2H, H-2 , H-6 ), 7.60 (dd, JZ8.1,
4.6 Hz, 1H, H-3), 8.55 (dd, JZ8.1, 1.7 Hz, 1H, H-4), 8.99
(dd, JZ4.6, 1.7 Hz, 1H, H-2), 9.01 (br s, 1H, OH). 130C
NMR (DMSO-d6): d 55.5 (O–CH3), 114.3 (C-30, C-5 ),
119.2 (C-7), 121.4 (C-4a), 122.8 (C-3), 128.1 (C-20, C-60),
133.9 (C-10), 136.2 (C-8), 136.6 (C-4), 148.0 (C-8a), 153.8
(C-2), 158.6 (C-40), 158.9 (C-5). Anal. Calcd for
C15H12N2O3$0.75H2O: C, 63.94; H, 4.83; N, 9.94. Found:
C, 63.98; H, 4.36; N, 9.97%.
(C-40). IR (nujol): 2227.7 cmK1
.
3.11.2. 3-Formyl[1,2,3]triazolo[1,5-a]pyridine-4-(4-
methoxyphenyl)carboxamide (16c). Diazonium salt 14c
(0.15 g, 0.41 mmol) was suspended in water (10 mL) and
10% NaOH (1 mL) was added. The mixture was stirred for
1 h, at which time the white solid was filtered and washed
with water to give 16c (0.10 g, 82%), mp 184–185 8C (from
MeCN). 1H NMR (DMSO-d6): d 3.73 (s, 3H, O–CH3), 6.93
(d, JZ8.8 Hz, 2H, H-30, H-50), 7.51 (t, JZ7.2 Hz, 1H, H-6),
7.62 (d, JZ8.8 Hz, 2H, H-20, H-60), 8.02 (d, JZ7.2 Hz, 1H,
H-5), 9.42 (d, JZ7.0 Hz, 1H, H-7), 10.22 (s, 1H, CHO),
10.48 (br s, 1H, NH). 13C NMR (DMSO-d6): d 55.3
(O–CH3), 114.0 (C-30, C-50), 117.2 (C-6), 121.9 (C-20,
C-60), 128.2 (C-4), 128.4 (C-7), 130.9 (C-3a), 130.9 (C-5),
131.8 (C-10), 136.9 (C-3), 156.0 (C-40), 162.8 (CO), 183.3
(CHO). Anal. Calcd for C15H12N4O3: C, 60.81; H, 4.08; N,
18.91. Found: C, 60.61; H, 4.18; N, 18.89%.
3.11.3. 4-Methyl-5-oxo-5,6-dihydro-3H-benzo[b][1,2,3]-
triazolo[4,5,1-ij][1,6]naphthyridin-3-ol (15a). To a solu-
tion of amine 6a (0.36 g, 1.60 mmol) in 43% HBF4 (5 mL) at
room temperature was added, dropwise, a solution of NaNO2
(0.13 g, 1.92 mmol) in water (3 mL). The resultant mixture
was stirred for 1 h, then filtered and washed with Et2O to give
a pink solid. This was suspended in MeCN (10 mL) and water
was added (1 mL). The mixture was stirred for 5 min, during
which time the color changed from pink to white, and
filtration gave 15a as a white solid (0.24 g, 59%), mp
235–239 8C (after darkening O187 8C), which partially
changed to 16a on standing or during attempted recrystalli-
A yellow solution in EtOH gave an intense green color on
addition of Fe3C
.
Acknowledgements
We thank Dr. Martha Kalkanidis for contributing some
work on the Hofmann reaction of 3b.
1
zation. H NMR (DMSO-d6): d 3.14 (s, 3H, N–CH3), 6.35
(d, JZ9.5 Hz, 1H, H-3), 7.11 (d, JZ9.5 Hz, 1H, OH), 7.76
(t, JZ7.7 Hz, 1H, H-9), 7.96 (t, JZ7.5 Hz, 1H, H-8), 8.29
(s, 1H, H-6), 8.33 (d, JZ7.8 Hz, 1H, H-10), 8.61 (d, JZ
8.2 Hz, 1H, H-7). 13C NMR (DMSO-d6): d 32.2 (N–CH3),
80.0 (C-3), 115.5 (C-7), 117.1 (C-5a), 125.0 (C-10a), 125.9
(C-6), 128.0 (C-9), 128.5 (C-11a), 131.7 (C-6a), 131.9
(C-10), 132.2 (C-8), 135.3 (C-2a), 159.2 (C-5).
References and notes
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3.11.4. N-Methyl-3-formyl[1,2,3]triazolo[1,5-a]quino-
line-4-carboxamide (16a). A suspension of 15a (0.18 g,
7.09 mmol) in water (10 mL) and 10% NaOH (1 mL) was

2320
L. W. Deady, S. M. Devine / Tetrahedron 62 (2006) 2313–2320
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