Synthesis of 7-substituted 3-aryl-l,6-naphthyridin-2-amines and 7-substituted 3-aryl-l,6-naphthyridin-2(1H)-ones via diazotization of 3-aryl-l ,6-naphthyridine-2,7-diamines

Article abstract of DOI:10.1039/b002599m

The preparation of 3-aryl-7-halo-l,6-naphthyridin-2-amines and 3-aryl-7-halo-l,6-naphthyridin-2(1H)-ones from the diazotization of 3-aryl-l,6-naphthyridine-2,7-diamines is reported. The reactions were investigated in various solvents (concentrated HC1, 50% HBF₄, 70% HF-pyridine, 20% and 90% H₂SO₄, dilute HC;, and neat TFA). By appropriate choice of solvent and other conditions, good yields of the target compounds could be obtained, although in some cases a variety of different side products was also produced. Subsequent displacement of the 7-halogen substituents with alkylamines provides a route to more complex 7-substituted 1,6-naphthyridine derivatives that are potential tyrosine kinase inhibitors. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b002599m

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Synthesis of 7-substituted 3-aryl-1,6-naphthyridin-2-amines and
7-substituted 3-aryl-1,6-naphthyridin-2(1H)-ones via diazotization
of 3-aryl-1,6-naphthyridine-2,7-diamines
1
Andrew M. Thompson,*a H. D. Hollis Showalterb and William A. Dennya
a Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences,
The University of Auckland, Private Bag 92019, Auckland, New Zealand
b Parke-Davis Pharmaceutical Research, Division of the Warner-Lambert Company,
2800 Plymouth Rd., Ann Arbor, Michigan 48106-1047, USA
Received (in Cambridge, UK) 3rd April 2000, Accepted 14th April 2000
Published on the Web 1st June 2000
The preparation of 3-aryl-7-halo-1,6-naphthyridin-2-amines and 3-aryl-7-halo-1,6-naphthyridin-2(1H)-ones
from the diazotization of 3-aryl-1,6-naphthyridine-2,7-diamines is reported. The reactions were investigated in
various solvents (concentrated HCl, 50% HBF4, 70% HF–pyridine, 20% and 90% H2SO4, dilute HCl, and neat
TFA). By appropriate choice of solvent and other conditions, good yields of the target compounds could be
obtained, although in some cases a variety of different side products was also produced. Subsequent displacement
of the 7-halogen substituents with alkylamines provides a route to more complex 7-substituted 1,6-naphthyridine
derivatives that are potential tyrosine kinase inhibitors.
alkylamino analogues as potential inhibitors of tyrosine kinase
Introduction
enzymes.1,2 The synthesis of (3-substituted) 1,6-naphthyridin-
2(1H)-ones commonly involves the condensation of 4-amino-
nicotinaldehyde 1 with substituted ethyl acetates, malonates or
malonamides.3,4 However, 3-phenyl-1,6-naphthyridin-2(1H)-
In current work we required 3-aryl-7-halo-1,6-naphthyridin-
2(1H)-ones 11 and 3-aryl-7-halo-1,6-naphthyridin-2-amines 12
as intermediates for the synthesis of various 7-substituted
Scheme 1 Literature background and proposed routes to 1,6-naphthyridine derivatives. Reagents and conditions: a, PhCH2CO2Et–piperidine–
EtOH (ref. 4); b, PhCH2CN–NaOH–EtOH–water (ref. 5); c, XPhCH2CN–Na–2-ethoxyethanol (ref. 6); d, NaNO2–50% HBF4 (ref. 15).
DOI: 10.1039/b002599m
J. Chem. Soc., Perkin Trans. 1, 2000, 1843–1852
This journal is © The Royal Society of Chemistry 2000
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Table 1 Results for the diazotization–fluorodediazoniation of 5b using either the modified Schiemann method, ‘A’ (NaNO2 in 50% HBF4) or
Fukuhara’s method, ‘B’ (NaNO2 in 70% HF–pyridine)
Scale
(Mass 5b/g)
Equiv.
NaNO2
Method
Reaction conditions
Products and yields (%)
A
A
A
A
A
B
0.25
1.0
1.55
4.0
2.0
0.25
8
8
8
8
4 h/0 ЊC, 2 d/Ϫ20 ЊC
5 h/0 ЊC, 4 d/Ϫ20 ЊC
5 h/Ϫ5 ЊC, 5 d/Ϫ20 ЊC
8 h/Ϫ5 ЊC, 6 d/Ϫ20 ЊC
18 (42), 14b (34), 19 (10), 20 (3)
18 (25), 14b (37), 19 (30), 20 (5)
19 (58), 20 (29)
19 (54), 20 (26)
1.6
8 then 16
4 h/Ϫ5 ЊC, 5 d/Ϫ20 ЊC
18 (55), 14b (33)
0.5 h/0 ЊC, 1 h/20 ЊC, 6 d/Ϫ20 ЊC,
then 1 h/0 ЊC, 6 h/20 ЊC, 3 d/Ϫ20 ЊC
0.5 h/0 ЊC, 1 h/20 ЊC, then 1 h/20 ЊC
18 (42), 19 (36), 23 (0.4), 24 (0.4),
25 (0.2)
B
0.10
1.7 then 0.5
18 (75)
one 2 was reported to be formed in very poor yield (21%)
despite reaction for several days4 (Scheme 1A), suggesting that
this was not a viable general route to the more complex com-
pounds 11. Related (3-substituted) 1,6-naphthyridin-2-amines
have been similarly prepared by the condensation of 1 with
variously substituted acetonitriles; in this case 3-phenyl-1,6-
naphthyridin-2-amine 3 was reported to be formed readily and
in high yield (68%) by the condensation of 1 with phenyl-
acetonitrile5 (Scheme 1A). In a similar fashion, a small series
of 3-(substituted phenyl)-1,6-naphthyridine-2,7-diamines 5 was
prepared6 in good yield from 4,6-diaminonicotinaldehyde 4
(Scheme 1B). However, compounds 12 were not directly avail-
able by this methodology because of the difficulty in preparing
the appropriate 4-amino-6-halonicotinaldehydes, and because
of the expected reactivity of the displaceable halogen substitu-
ent during the base catalysed condensation reaction.
nickel reduction of 4,6-diaminonicotinonitrile17) with substi-
tuted phenylacetonitriles in boiling 2-ethoxyethanol in the
presence of the sodium alkoxide (Scheme 1B), as described
previously.6,18
Reaction of 3-phenyl-1,6-naphthyridine-2,7-diamine 5a in
concentrated HCl (HCl saturated) with a large excess of solid
NaNO2 (8 equivalents) at Ϫ10 to ϩ20 ЊC, gave a readily
separable mixture of mostly 7-chloro-3-phenyl-1,6-naphth-
yridin-2-amine 13a (61%) and 2-amino-3-phenyl-1,6-naph-
thyridin-7(6H)-one 14a (19%). However, minor amounts of
15a and 16a, resulting from ring chlorination at C-8, were also
obtained (1 and 5%, respectively) (Scheme 2A). The 2-amino
group appeared essentially inert under these conditions, despite
the large excess of reagent, enabling selective diazotization of
the 7-amine. This large differential in reactivity was ascribed
to the steric hindrance of the 2-amine by the neighbouring
3-phenyl group. Reaction of 3-(2,6-dichlorophenyl)-1,6-naph-
thyridine-2,7-diamine 5b under the same conditions gave
analogous results (compounds 13b–16b), but with slightly lower
yields, along with small amounts of recovered starting material
and its 8-chloro derivative 17. Thus the direct preparation of a
2,7-dichloro derivative 10 (X = H or 2,6-diCl, hal = Cl) was not
feasible under these conditions.
Diamine 5a was then treated with a large excess of solid
NaNO2 in 90% H2SO4, in an attempt to prepare the dione 9
(X = H) for potential conversion to the corresponding 2,7-
dihalo derivative 10 (X = H). However, a complex mixture
resulted, in which 14a could be detected but not separated.
Similar results were obtained with analogous reactions in dilute
HCl, 20% H2SO4, and neat TFA, indicating the unsuitability of
this approach.
The observed byproducts in the diazotization of 5a and 5b in
concentrated HCl, together with the desire for a more easily
displaced halogen substituent than chlorine, led us to examine
the modified Schiemann method.14 The results of various
reactions of 5b with NaNO2 in 50% HBF4 are summarized in
Table 1 and Scheme 2B. An initial small scale reaction (0.25 g)
with excess NaNO2 (Table 1, entry 1) gave mainly 3-(2,6-
dichlorophenyl)-7-fluoro-1,6-naphthyridin-2-amine 18 (42%
yield) and 2-amino-3-(2,6-dichlorophenyl)-1,6-naphthyridin-
7(6H)-one 14b (34% yield), similar to the results above using
HCl. However, when the scale of the reaction was increased
(keeping concentrations the same) and the reaction mixture
was left for longer times at Ϫ20 ЊC prior to workup, increasing
amounts of 3-(2,6-dichlorophenyl)-7-fluoro-1,6-naphthyridin-
2(1H)-one 19 and 3-(2,6-dichlorophenyl)-1,6-naphthyridin-
2,7(1H,6H)-dione 20 were formed, and were the eventual sole
reaction products (54–58% and 26–29% yields respectively;
Table 1, entries 3 and 4).
There have been several reports7–11 of the facile and high
yielding preparation of 1,8-naphthyridin-2(1H)-ones (includ-
ing 3-phenyl analogues) by diazotization of the corresponding
2-amino derivatives in 2 M HCl, concentrated H2SO4, 40%
H2SO4 and TFA. The preparation of 2-halopyridines by the
diazotization–halodediazoniation of 2-aminopyridines is also
well established.12–14 For example, we have recently employed a
modified Schiemann method14 (NaNO2–50% HBF4) to diazo-
tize 7-aminopyrido[4,3-d]pyrimidin-4(3H)-one 6 to a 3:2 mix-
ture of 7-fluoro- and 7(6H)-one derivatives (7 and 8)15 (Scheme
1C). We therefore envisaged that double diazotization of
3-(substituted phenyl)-1,6-naphthyridine-2,7-diamines 5 would
enable the preparation of key 2,7-dihalo derivatives 10, either
directly, or indirectly via the halogenation of 1,6-naphthyridine-
2,7(1H,6H)-diones 9, as reported8 in the 1,8-naphthyridine
series (Scheme 1D). We expected that the two halogen
substituents in 10 would display quite different reactivities
toward nucleophiles (or hydrolysis to give 11) on the basis
of our experiences with amine displacements in isomeric
fluoropyrido[d]pyrimidines15 and the results of Chapman and
Russell-Hill,16 who reported that the chloro substituents of
2-chloroquinoline and 3-chloroisoquinoline differed markedly
in reaction rate toward displacement by ethoxide (a factor of
5 × 104), with 3-chloroisoquinoline being virtually unactivated.
Alternatively,
a selective diazotization–halodediazoniation
of the 7-amino group would enable direct preparation of the
desired 3-aryl-7-halo-1,6-naphthyridin-2-amines 12, and thus
a potential two step synthesis of the 3-aryl-7-halo-1,6-naph-
thyridin-2(1H)-ones 11 (Scheme 1E).
We report here studies on the diazotization of various
3-(substituted phenyl)-1,6-naphthyridine-2,7-diamines 5 using
a range of solvents and conditions, and discuss the varying
reactivities of the halogen substituted products towards amine
displacement.
The formation of 19 but not the 2,7-difluoro derivative 24
under these conditions suggests that the initially formed
2-fluorine substituent is very reactive, hydrolysing in situ during
the reaction and/or subsequent workup (although some 19
could also arise from 18 by direct hydrolysis of the 2-diazonium
salt). This is consistent with the results of Hawes and Gorecki,3
who found that the chlorine of 2-chloro-3-cyano-1,6-naph-
Results and discussion
The required 3-(substituted phenyl)-1,6-naphthyridine-2,7-
diamines 5 were prepared in excellent yield by the condensation
of the known1,6 4,6-diaminonicotinaldehyde 4 (from Raney
1844
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Scheme 2 Reagents and conditions: a, NaNO2–conc. HCl; b, NaNO2–50% HBF4; c, MeNH2–2-PrOH (ref. 3); d, NaNO2–70% HF–pyridine; e,
NaNO2–TFA.
thyridine 21 was easily displaced by nucleophiles (e.g., MeNH2,
1 h at 20 ЊC to give 22, Scheme 2C), and a fluorine substituent
should be even more reactive. Preliminary attempts to activate
20 to the 2,7-dichloro derivative 10 (X = 2,6-diCl, hal = Cl)
using POCl3 or SOCl2 were unsuccessful, although the method
used by Hawes and Gorecki3 in the preparation of 21 (PCl5–
POCl3) from the corresponding 1,6-naphthyridin-2(1H)-one
was not examined. The best conditions found for the prepar-
ation of 18 (55% yield) using the modified Schiemann method
(Table 1, entry 5) involved the diazotization of 5b with a small
excess (1.6 equivalents) of NaNO2 in 50% HBF4 (with 1.1
equivalents of NaNO2, unreacted 5b could still be detected by
TLC after 3 days at Ϫ20 ЊC). However, it should be noted that
the reaction times employed here were not optimized, and with
more careful monitoring it may be possible to reduce these
considerably.
The above methodology was not suitable for elaboration of
the corresponding 3-(3,5-dimethoxyphenyl)-1,6-naphthyridine-
2,7-diamine 5c, which contained a more electron-rich phenyl
ring. Reaction of 5c in 50% HBF4 with varying stoichiometries
of NaNO2 gave only complex mixtures of products, many of
which were unstable. From a reaction employing 1.5 equivalents
of NaNO2, two products were isolated in very low yield (each
ca. 3%) following extensive chromatography (Scheme 3A). The
less polar compound was the desired 3-(3,5-dimethoxyphenyl)-
7-fluoro-1,6-naphthyridin-2-amine 26 by HREIMS and 1H
NMR. The more polar compound 27 was the 2Ј-nitro derivative
of 26, resulting from nitrosation of the electron-rich 3,5-
dimethoxyphenyl ring, followed by aerial oxidation. A larger
scale reaction using 8 equivalents of NaNO2 gave small
amounts of only two isolable products (each 4% yield), the
quinone derivative 28 and a compound which is probably
(based on NMR, HREIMS and analytical data) the quinone
imine derivative 29 (Scheme 3A). Compound 28 could arise
from 26 by diazotization–hydrolysis at C-2, nitrosation at
C-2Ј, demethylation of the 5Ј-methoxy group, and oxidation/
hydrolysis. Similarly, compound 29 could arise from nitrosation
(twice), demethylation of one methoxy group, (partial) oxid-
ation and O-coupling of one NO group at C-2, either by dis-
placement of a 2-fluorine substituent or a 2-diazonium salt.
Reaction of 5c with excess NaNO2 in concentrated HCl also
gave a complex mixture of products.
Recently it has been demonstrated that fluoropyridines can
be prepared in considerably higher yields by diazotization–
fluorodediazoniation of the amino derivative in HF–pyridine.19
This is likely to be due at least in part to the more anhydrous
nature of this solvent system (which reduces the proportion of
hydrolysis), since recycling the HF–pyridine reportedly lowered
its activity, due to increased water content from the diazotiz-
ation and consumption of HF.20 We expected that these
conditions offered the best possibility for the isolation of the
2,7-difluoro derivative 24 from 5b, as well as for the formation
of 18 and/or 19 in higher yield.
Reaction of 5b with a large excess of NaNO2 in 65–70% HF–
pyridine (monitored by TLC) gave rapid formation of 18 (com-
plete after 1 h at 20 ЊC), then very slow further conversion to 19
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Scheme 3 Reagents and conditions: a, NaNO2–50% HBF4; b, NaNO2–70% HF–pyridine, pyridine; c, NaOH–water–THF, 53 ЊC, 3 days.
(Table 1, entry 6) which, on a small scale (0.25 g), could not be
forced to completion. Separation of the major products gave 18
(42%) and 19 (36%), along with a mixture of three less polar
components (2.5 mg) which were further separated by prepar-
ative TLC. The least polar of these (Scheme 2D) was 2-chloro-
3-(2,6-dichlorophenyl)-7-fluoro-1,6-naphthyridine 23 (0.4%), as
are known to be many orders of magnitude more reactive
towards nucleophilic displacement than the corresponding
α-halo quinolines.22 An improved yield of 18 (75%) was
obtained on a small scale by the diazotization of 5b with a small
excess (2.2 equivalents) of NaNO2 in 65–70% HF–pyridine
(Table 1, entry 7) (with 1.7 equivalents of NaNO2, unreacted 5b
could still be detected by TLC after 1 h at 20 ЊC). We then
examined the further diazotization of 18 to 19 under altern-
ative reaction conditions (for comparison with the modified
Schiemann method). Surprisingly, diazotization of 18 with
NaNO2 in neat TFA10 (2.5 h at 20 ЊC) gave an almost quanti-
tative conversion to 19 (96%) on a small scale (little reaction
was observed at 0 ЊC). Therefore this two step procedure
(Schemes 2D, 2E) for the preparation of 19 (employing a small
excess of NaNO2 in the first step) is preferred over the modified
Schiemann method.
Small scale treatment of 5c under similar conditions (Scheme
3B), employing a small excess (2.1 equivalents) of NaNO2 in
65–70% HF–pyridine at Ϫ5 ЊC, unexpectedly gave an excellent
yield of 3-(3,5-dimethoxyphenyl)-7-fluoro-1,6-naphthyridin-2-
amine 26 (81%), together with the hydrolysis product, 2-amino-
3-(3,5-dimethoxyphenyl)-1,6-naphthyridin-7(6H)-one 30 (15%)
and a small amount of 2,7-difluoro-3-(3,5-dimethoxyphenyl)-
1,6-naphthyridine 31 (4%). However, the reaction was found to
be very sensitive to the exact condition of the HF–pyridine
employed, since a larger scale reaction using a fresh batch of
reagent (fuming with HF, unlike the older batch used in the
reactions above) gave almost complete decomposition (<6%
yield of crude 26). In contrast, when this fresh HF–pyridine
was diluted with dry pyridine, diazotization was much slower
(requiring several hours at 20 ЊC), but even more effective
(being more anhydrous). Thus, with a slightly larger excess of
1
shown by HREIMS and H NMR, and may have arisen from
displacement of the 2-fluorine of 24 by adventitious chloride
ion, due to possible salt contamination of the salt–ice cooled
reaction solution just prior to or during workup. The second
component was the desired 3-(2,6-dichlorophenyl)-2,7-difluoro-
1,6-naphthyridine 24 (0.4%), identified by the characteristically
large meta HF coupling to H-4 in the 1H NMR (9.8 Hz) and by
HREIMS. The most polar component was 3-(2,6-dichloro-
phenyl)-7-fluoro-2-nitro-1,6-naphthyridine 25 (0.2%), identified
by HREIMS (showing characteristic loss of NO2 and NO from
the parent ion) and the strongly downfield 1H NMR resonances
for H-4, 5 and 8 (0.2–0.3 ppm further downfield than observed
for 24). This compound is probably formed by direct displace-
ment of the diazonium salt (or possibly the 2-fluorine) by nitrite
ion (present in a very large excess). Overall, the yield of fluorin-
ated products was much higher with HF–pyridine than aqueous
HBF4, and neutralization of the final product solution was also
easier in this system.
The 2,7-difluoro compound 24 was stable in neutral aqueous
MeOH (20 ЊC, 1 h) and (aqueous) DMSO (20 ЊC, several
hours). Therefore the low yield of 24 from the above reaction,
relative to the amount of the hydrolysis product 19 observed, is
probably due simply to the general acid catalysis of nucleophilic
displacements from basic heterocyclic systems as previously
reported.16,21 Protonation of N-1 could cause behaviour more
similar to that of α-halo quaternary quinolinium salts, which
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Scheme 4 Reagents and conditions: 1-(3-aminopropyl)-4-methylpiperazine: a, neat, 160 ЊC, 3–5 days; b, 2-ethoxyethanol, 135 ЊC, 5 days; c, pentan-
2-ol, 118 ЊC, 15 h.
NaNO2 (3 equivalents), a higher yield of the difluoro derivative
31 was obtained (18%), together with a comparable yield of 26
(78%), and a very small amount of 3-(3,5-dimethoxyphenyl)-7-
fluoro-1,6-naphthyridin-2(1H)-one 32 (2%).
Reaction of 3-(3,5-dimethoxyphenyl)-7-fluoro derivative 26 in
boiling 2-ethoxyethanol was slower than that of 18, requiring a
larger excess of amine (40 equivalents for 5 days), but gave the
7-substituted derivative 37 in comparable purified yield (43%).
Finally, reaction of the more electron-deficient 7-fluoro-1,6-
naphthyridin-2(1H)-one 19 in boiling pentan-2-ol (118 ЊC for
15 h) was even more facile and gave an excellent yield (82%) of
the 7-substituted derivative 38.
In conclusion, we have investigated the diazotization chem-
istry of 3-aryl-1,6-naphthyridine-2,7-diamines and shown that,
by variation of the reaction conditions, good yields of either
3-aryl-7-halo-1,6-naphthyridin-2(1H)-ones 11 or 3-aryl-7-halo-
1,6-naphthyridin-2-amines 12 can be obtained. This opens the
way to the synthesis of more complex 7-substituted 1,6-naph-
thyridine derivatives.
Diazotization of 26 with NaNO2 in neat TFA was ineffective
as a route to 32, as expected (due to the strong acidity of this
solvent), giving a low yield (28%) of the 2Ј-nitro derivative 27
as the only isolable product. However, partial hydrolysis of di-
fluoro compound 31 (NaOH–water–THF, 20 or 53 ЊC) gave 32
essentially quantitatively (Scheme 3C). This provides a poten-
tially efficient two step synthesis of 32, since the yield of
difluoro derivative 31 could clearly be optimized by further
diazotization of 26 (and 5c) under the improved conditions
described (fresh 70% HF–pyridine diluted with pyridine, using
larger excesses of NaNO2 and/or longer reaction times). Partial
hydrolysis of 31 was also demonstrated under these (still acidic)
diazotization reaction conditions (without NaNO2) in the pres-
ence of added water, although purified 31 had extremely poor
solubility in this solvent mixture, accounting for an incomplete
reaction (54% conversion to 32 after 2 days at 20 ЊC, with 45%
recovered 31).
The reactivity of the various halogenated naphthyridines
with the amine nucleophile 1-(3-aminopropyl)-4-methylpiper-
azine was also examined (Scheme 4). Reaction of the 7-chloro-
3-phenyl analogue 13a required forcing conditions (neat amine
at 160 ЊC for 5 days) and gave predominantly the 2,7-bis-
substitution product 33 (60%), together with a small amount of
the expected 2-amino-7-substituted derivative 34 (7.5%). Simi-
lar reaction of the 7-chloro-3-(2,6-dichlorophenyl) derivative
13b (160 ЊC for 3 days) gave a higher yield of the 2-amino-7-
substituted derivative 35 (44%). As expected, the 7-fluoro
derivative 18 was significantly more reactive than 13b, undergo-
ing displacement in boiling 2-ethoxyethanol (135 ЊC for 5 days)
to give 35 (46%), together with a small amount of the 7-(4-
methylpiperazine) derivative 36 (6%) [the latter was prepared
independently in high yield (78%) by treatment of 18 with
1-methylpiperazine in boiling pentan-2-ol (118 ЊC for 7 days)].
Experimental
Analyses were performed by the Microchemical Laboratory,
University of Otago, Dunedin, NZ. Melting points were deter-
mined using an Electrothermal Model 9200 digital melting
point apparatus, and are as read. Routine NMR spectra were
measured on a Bruker DRX-400 spectrometer at 400 MHz (1H)
or 100 MHz (13C), with Me4Si as an internal standard, and
J values are given in Hz. Mass spectra were determined on a
VG-70SE mass spectrometer at nominal 5000 resolution. Light
petroleum refers to the fraction boiling at 40–60 ЊC. Reactions
using HF–pyridine were optimally conducted in capped plastic
vials.
3-Phenyl-1,6-naphthyridine-2,7-diamine 5a
4,6-Diaminonicotinaldehyde hydrochloride was prepared from
the free base 41 by taking the filtered solution from the
reported6 hydrogenation of the precursor nitrile17 (26 g in
160 cm3 of water and 80 cm3 of formic acid) and diluting it with
conc. HCl (40 cm3). The mixture was evaporated to a brown
J. Chem. Soc., Perkin Trans. 1, 2000, 1843–1852
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powder that was triturated in Et2O. The solid was collected and
recrystallized from water to give the hydrochloride of 4 (13 g),
mp >200 ЊC (decomp.). A mixture of this hydrochloride (13 g,
74.9 mmol) and phenylacetonitrile (11.5 g, 98.2 mmol) in
2-ethoxyethanol (100 cm3) was treated with a solution of
NaOMe (5.60 g, 104 mmol) in 2-ethoxyethanol (100 cm3). The
resultant mixture was stirred under reflux for 3 h, cooled, and
concentrated. The residue was triturated in cold water contain-
ing a few drops of dilute aq. NaOH, and the resultant solids
were collected by filtration, washed with cold water and air
dried to leave 18.4 g of crude product. Further purification by
double crystallization afforded pure diamine 5a (10.5 g, 59%),
mp 200–201 ЊC (from EtOH) (Found: C, 71.4; H, 4.9; N, 24.0.
C14H12N4 requires C, 71.2; H, 5.1; N, 23.7%); δH([2H6]DMSO)
8.43 (1 H, s, 5-H), 7.65 (1 H, s, 4-H), 7.48 (4 H, m, 2Ј,3Ј,5Ј,6Ј-
H), 7.40 (1 H, m, 4Ј-H), 6.31 (1 H, s, 8-H), 6.26 (2 H, br s,
2-NH2), 5.91 (2 H, br s, 7-NH2); δC([2H6]DMSO) 159.59, 158.30
(2 s, 2,7-C), 152.64 (s, 8a-C), 150.37 (d, 5-C), 137.59 (s, 1Ј-C),
136.01 (d, 4-C), 128.88, 128.60 (2 × 2 C, 2 d, 2Ј,3Ј,5Ј,6Ј-C),
127.51 (d, 4Ј-C), 120.96 (s, 3-C), 113.52 (s, 4a-C), 95.54 (d, 8-C).
5-C), 148.29 (s, 7-C), 136.36 (s, 1Ј-C), 135.59 (d, 4-C), 129.02,
128.54 (2 × 2 C, 2 d, 2Ј,3Ј,5Ј,6Ј-C), 128.32 (d, 4Ј-C), 126.49 (s,
3-C), 118.90 (s, 4a-C), 116.58 (d, 8-C); m/z (HREIMS)
257.0529, 255.0555 (Mϩ, C14H10ClN3 requires 257.0534,
255.0563).
Further elution with 5–10% MeOH–CH2Cl2 gave 2-amino-8-
chloro-3-phenyl-1,6-naphthyridin-7(6H)-one 16a (58 mg, 5%),
mp 318–321 ЊC (from MeOH–CH2Cl2–hexane) (Found: C,
61.8; H, 3.4; N, 15.6. C14H10ClN3O requires C, 61.9; H, 3.7;
N, 15.5%); δH([2H6]DMSO) 12.29 (1 H, br s, NH), 8.14 (1 H, s,
5-H), 7.66 (1 H, s, 4-H), 7.49 (2 H, t, J 7.3, 3Ј,5Ј-H), 7.43 (3 H,
m, 2Ј,4Ј,6Ј-H), 7.00 (2 H, br s, NH2); m/z (HREIMS) 273.0481,
271.0504 (Mϩ, C14H10ClN3O requires 273.0483, 271.0512).
Further elution with 10–12% MeOH–CH2Cl2 gave 2-amino-
3-phenyl-1,6-naphthyridin-7(6H)-one 14a (187 mg, 19%),
mp 270–276 ЊC (decomp.) (from MeOH–CH2Cl2–hexane)
(Found: C, 68.7; H, 4.9; N, 17.1. C14H11N3Oؒ0.5H2O requires
C, 68.3; H, 4.9; N, 17.1%); δH([2H6]DMSO) 11.37 (1 H, br s,
NH), 8.23 (1 H, s, 5-H), 7.64 (1 H, s, 4-H), 7.49 (2 H, t,
J 7.2, 3Ј,5Ј-H), 7.42 (3 H, m, 2Ј,4Ј,6Ј-H), 6.59 (2 H, br s, NH2),
6.13 (1 H, s, 8-H); δC([2H6]DMSO) 163.03 (s, 7-C), 159.05 (s,
2-C), 154.75 (s, 8a-C), 142.57 (br d, 5-C), 136.87 (s, 1Ј-C),
136.09 (d, 4-C), 128.89, 128.57 (2 × 2 C, 2 d, 2Ј,3Ј,5Ј,6Ј-C),
127.83 (d, 4Ј-C), 122.91 (s, 3-C), 111.69 (s, 4a-C), 100.63 (d,
8-C); m/z (HREIMS) 237.0903 (Mϩ, C14H11N3O requires
237.0902).
3-(3,5-Dimethoxyphenyl)-1,6-naphthyridine-2,7-diamine 5c
3,5-Dimethoxyphenylacetonitrile (5.80 g, 32.8 mmol) and 41
(3.90 g, 28.5 mmol) were added to a solution of sodium (0.69 g,
30.0 mmol) dissolved in 2-ethoxyethanol (30 cm3), then the
mixture was stirred under reflux for 30 min. The cooled solution
was treated with ice–aqueous NaHCO3 and extracted with
EtOAc (12 × 200 cm3). The extracts were evaporated to dryness
and the residue was then chromatographed on silica gel. Elu-
tion with 0–2% MeOH–CH2Cl2 gave minor impurities, then
elution with 3–7% MeOH–CH2Cl2 gave the diamine 5c (8.06 g,
96%), mp 229–232 ЊC (from MeOH–CHCl3–light petroleum)
(Found: C, 63.7; H, 5.3; N, 18.3. C16H16N4O2ؒ0.25H2O requires
C, 63.9; H, 5.5; N, 18.6%); δH([2H6]DMSO) 8.41 (1 H, s, 5-H),
7.67 (1 H, s, 4-H), 6.59 (2 H, d, J 2.2, 2Ј,6Ј-H), 6.52 (1 H, t,
J 2.2, 4Ј-H), 6.31 (2 H, br s, 2-NH2), 6.29 (1 H, s, 8-H), 5.90
(2 H, br s, 7-NH2), 3.79 (6 H, s, 2 × OCH3); δC([2H6]DMSO)
160.63 (2 C, s, 3Ј,5Ј-C), 159.58, 158.14 (2 s, 2,7-C), 152.62 (s,
8a-C), 150.36 (d, 5-C), 139.50 (s, 1Ј-C), 135.75 (d, 4-C), 120.86
(s, 3-C), 113.31 (s, 4a-C), 106.52 (2 C, d, 2Ј,6Ј-C), 99.70 (d,
4Ј-C), 95.49 (d, 8-C), 55.16 (2 C, q, 2 × OCH3).
Diazotization of 3-(2,6-dichlorophenyl)-1,6-naphthyridine-2,7-
diamine 5b
(a) In HCl. A solution of 5b1,6 (249 mg, 0.816 mmol) in 37%
HCl (10 cm3) at 0 ЊC was saturated with gaseous HCl, then
treated with solid NaNO2 (0.45 g, 6.52 mmol) and stirred at
0 ЊC for 4 h, then kept at Ϫ20 ЊC for 2 days. The resulting mixture
was neutralized with solid Na2CO3–ice, keeping the temperature
below 0 ЊC, and extracted with EtOAc (3 × 100 cm3). The sol-
vent was removed, then chromatography of the residue on silica
gel, eluting with 20% light petroleum–CH2Cl2 and CH2Cl2, gave
firstly 7,8-dichloro-3-(2,6-dichlorophenyl)-1,6-naphthyridin-2-
amine 15b (9 mg, 3%), mp 251–253.5 ЊC (from MeOH–water);
δH([2H6]DMSO) 8.72 (1 H, s, 5-H), 8.08 (1 H, s, 4-H), 7.64 (2 H,
d, J 8.2, 3Ј,5Ј-H), 7.53 (1 H, dd, J 8.9 and 7.4, 4Ј-H), 7.40 (2 H,
br s, NH2); δC([2H6]DMSO) 159.10 (s, 2-C), 149.47 (s, 8a-C),
148.43 (d, 5-C), 146.55 (s, 7-C), 137.48 (d, 4-C), 134.67 (2 C, s,
2Ј,6Ј-C), 132.98 (s, 1Ј-C), 131.41 (d, 4Ј-C), 128.71 (2 C, d, 3Ј,5Ј-
C), 122.48 (s, 3-C), 121.94 (s, 8-C), 118.87 (s, 4a-C); m/z
(HREIMS) 360.9339, 358.9368, 356.9396 (Mϩ, C14H7Cl4N3
requires 360.9335, 358.9365, 356.9394).
Further elution with 0.5% MeOH–CH2Cl2 gave 7-chloro-3-
(2,6-dichlorophenyl)-1,6-naphthyridin-2-amine 13b (129 mg,
49%), mp 216–218 ЊC (from CH2Cl2–light petroleum) (Found:
C, 51.7; H, 2.2; N, 13.0; Cl, 33.1. C14H8Cl3N3 requires C, 51.8;
H, 2.5; N, 13.0; Cl, 32.8%); δH([2H6]DMSO) 8.77 (1 H, s, 5-H),
8.00 (1 H, s, 4-H), 7.64 (2 H, d, J 8.0, 3Ј,5Ј-H), 7.52 (1 H, dd,
J 8.9 and 7.4, 4Ј-H), 7.39 (1 H, s, 8-H), 7.00 (2 H, br s, NH2);
δC([2H6]DMSO) 158.73 (s, 2-C), 153.10 (s, 8a-C), 151.06 (d,
5-C), 148.80 (s, 7-C), 136.90 (d, 4-C), 134.71 (2 C, s, 2Ј,6Ј-C),
133.36 (s, 1Ј-C), 131.22 (d, 4Ј-C), 128.64 (2 C, d, 3Ј,5Ј-C), 121.94
(s, 3-C), 118.14 (s, 4a-C), 116.70 (d, 8-C).
Diazotization of 3-phenyl-1,6-naphthyridine-2,7-diamine 5a
A solution of 5a (1.00 g, 4.24 mmol) in 37% HCl (10 cm3) at
Ϫ15 ЊC was saturated with gaseous HCl, then treated with solid
NaNO2 (2.30 g, 33.3 mmol) and stirred at Ϫ10 ЊC for 5 h, then
at 20 ЊC for 3 h, and kept at 4 ЊC for 2 days. The resulting mixture
was cooled to Ϫ15 ЊC and neutralized with solid Na2CO3–ice,
keeping the temperature below Ϫ10 ЊC. The resulting solid
(0.98 g) was collected by filtration and washed with water.
Extraction of the filtrate with EtOAc (3 × 100 cm3) and
removal of the solvent gave further material, which was com-
bined with the above solid. Chromatography on silica gel, elut-
ing with CH2Cl2, gave firstly 7,8-dichloro-3-phenyl-1,6-naph-
thyridin-2-amine 15a (10 mg, 1%), mp 271–274 ЊC (from
MeOH–CH2Cl2–hexane); δH([2H6]DMSO) 8.72 (1 H, s, 5-H),
8.04 (1 H, s, 4-H), 7.51 (5 H, m, 2Ј,3Ј,4Ј,5Ј,6Ј-H), 7.30 (2 H, br s,
NH2); δC([2H6]DMSO) 159.81 (s, 2-C), 148.86 (s, 8a-C), 148.47
(d, 5-C), 146.03 (s, 7-C), 136.08 (d, 4-C), 135.94 (s, 1Ј-C), 129.20
(2 C, d, 3Ј,5Ј-C), 128.62 (3 C, d, 2Ј,4Ј,6Ј-C), 127.05 (s, 3-C),
121.90 (s, 8-C), 119.73 (s, 4a-C); m/z (HREIMS) 291.0130,
289.0163 (Mϩ, C14H9Cl2N3 requires 291.0144, 289.0174).
Further elution with 1% MeOH–CH2Cl2 gave crude 8-chloro-
3-(2,6-dichlorophenyl)-1,6-naphthyridine-2,7-diamine 17 (8.5
mg, 3%) as an oil; δH([2H6]DMSO) 8.40 (1 H, s, 5-H), 7.73 (1 H,
s, 4-H), 7.60 (2 H, d, J 8.0, 3Ј,5Ј-H), 7.47 (1 H, dd, J 8.7 and 7.5,
4Ј-H), 6.75 (2 H, br s, NH2), 6.34 (2 H, br s, NH2); m/z
(HREIMS) 341.9847, 339.9871, 337.9894 (Mϩ, C14H9Cl3N4
requires 341.9834, 339.9863, 337.9893).
Further elution with 4% MeOH–CH2Cl2 gave recovered 5b
(2.4 mg, 1%).
Further elution with 4–5% MeOH–CH2Cl2 gave 2-amino-8-
chloro-3-(2,6-dichlorophenyl)-1,6-naphthyridin-7(6H)-one 16b
Further elution with 1–2% MeOH–CH2Cl2 gave 7-chloro-3-
phenyl-1,6-naphthyridin-2-amine 13a (660 mg, 61%), mp 206–
208 ЊC (from MeOH–CH2Cl2–hexane) (Found: C, 65.9; H, 3.8;
N, 16.7. C14H10ClN3 requires C, 65.8; H, 3.9; N, 16.4%);
δH([2H6]DMSO) 8.77 (1 H, s, 5-H), 7.98 (1 H, s, 4-H), 7.51 (5 H,
m, 2Ј,3Ј,4Ј,5Ј,6Ј-H), 7.39 (1 H, s, 8-H), 6.94 (2 H, br s, NH2);
δC([2H6]DMSO) 159.39 (s, 2-C), 152.43 (s, 8a-C), 151.00 (d,
1848
J. Chem. Soc., Perkin Trans. 1, 2000, 1843–1852

View Article Online
(13 mg, 5%), mp 325–330 ЊC (decomp.) (from MeOH–CHCl3–
light petroleum); δH([2H6]DMSO) 12.35 (1 H, br s, NH), 8.15
(1 H, s, 5-H), 7.65 (1 H, s, 4-H), 7.60 (2 H, d, J 8.1, 3Ј,5Ј-H), 7.48
(1 H, dd, J 8.7 and 7.5, 4Ј-H), 7.15 (2 H, br s, NH2); m/z
(HRFABMS) 343.9763, 341.9789, 339.9824 (MHϩ, C14H9Cl3-
N3O requires 343.9752, 341.9782, 339.9811).
JC-F 19, 5-C), 136.98 (d, 4-C), 134.82 (2 C, s, 2Ј,6Ј-C), 133.46 (s,
1Ј-C), 131.18 (d, 4Ј-C), 128.63 (2 C, d, 3Ј,5Ј-C), 121.05 (s, 3-C),
117.77 (d, JC-F 2.4, 4a-C), 99.68 (dd, JC-F 36, 8-C).
Further elution with 9–15% MeOH–CH2Cl2 gave 14b (0.67 g,
33%).
Further elution with 10–15% MeOH–CH2Cl2 gave 2-amino-
3-(2,6-dichlorophenyl)-1,6-naphthyridin-7(6H)-one 14b (68 mg,
27%), mp >260 ЊC (decomp.) (from MeOH) (Found: C, 54.6; H,
2.6; N, 13.7. C14H9Cl2N3O requires C, 54.9; H, 3.0; N, 13.7%);
δH([2H6]DMSO) 11.45 (1 H, br s, NH), 8.24 (1 H, s, 5-H), 7.61
(1 H, s, 4-H), 7.60 (2 H, d, J 8.4, 3Ј,5Ј-H), 7.47 (1 H, dd, J 8.7
and 7.3, 4Ј-H), 6.68 (2 H, br s, NH2), 6.12 (1 H, s, 8-H);
δC([2H6]DMSO) 163.24 (s, 7-C), 158.47 (s, 2-C), 155.41 (s, 8a-
C), 142.36 (br d, 5-C), 137.52 (d, 4-C), 135.22 (2 C, s, 2Ј,6Ј-C),
133.87 (s, 1Ј-C), 131.08 (d, 4Ј-C), 128.66 (2 C, d, 3Ј,5Ј-C), 118.55
(s, 3-C), 110.78 (s, 4a-C), 100.96 (d, 8-C).
(d) In HF–pyridine–excess NaNO2. A stirred suspension of 5b
(250 mg, 0.82 mmol) in 65–70% HF–pyridine (10 cm3) at 0 ЊC
was treated with solid NaNO2 (0.45 g, 6.52 mmol, added in
portions over 30 min), then stirred at 0 ЊC for 1 h, then at 20 ЊC
for 1 h and kept at Ϫ20 ЊC for 6 days. The mixture was further
treated with solid NaNO2 (0.90 g, 13.0 mmol, added in portions
over 1 h) at 0 ЊC, then stirred at 20 ЊC for 6 h and kept at Ϫ20 ЊC
for 3 days. The resulting mixture was neutralized with solid
Na2CO3–ice, keeping the temperature below Ϫ10 ЊC, diluted
with water (to 350 cm3) and extracted with EtOAc (7 × 100
cm3). The solvent was removed, then chromatography of the
residue on neutral alumina, eluting with CH2Cl2, gave firstly an
oil (2.5 mg), which was further purified by preparative silica gel
TLC (developed three times in 2% EtOAc–light petroleum).
Three bands were recovered and each was eluted with CH2Cl2.
The least polar component was 2-chloro-3-(2,6-dichloro-
phenyl)-7-fluoro-1,6-naphthyridine 23 (1.0 mg, 0.4%), isolated
as an oil; δH([2H6]DMSO) 9.32 (1 H, s, 5-H), 8.87 (1 H, s, 4-H),
7.81 (1 H, s, 8-H), 7.73 (2 H, d, J 8.3, 3Ј,5Ј-H), 7.62 (1 H, dd,
J 8.9 and 7.4 Hz, 4Ј-H); m/z (HREIMS) 329.9531, 327.9560,
325.9583 (Mϩ, C14H6Cl3FN2 requires 329.9522, 327.9551,
325.9581).
The central component was 3-(2,6-dichlorophenyl)-2,7-
difluoro-1,6-naphthyridine 24 (1.0 mg, 0.4%), isolated as an oil;
δH([2H6]DMSO) 9.31 (1 H, s, 5-H), 9.00 (1 H, d, JH-F 9.8, 4-H),
7.74 (1 H, s, 8-H), 7.74 (2 H, d, J 8.1, 3Ј,5Ј-H), 7.62 (1 H, dd,
J 8.9 and 7.4, 4Ј-H); m/z (HREIMS) 313.9824, 311.9846,
309.9876 (Mϩ, C14H6Cl2F2N2 requires 313.9817, 311.9847,
309.9876).
The most polar component was 3-(2,6-dichlorophenyl)-7-
fluoro-2-nitro-1,6-naphthyridine 25 (0.5 mg, 0.2%) as an oil;
δH([2H6]DMSO) 9.51 (1 H, s, 5-H), 9.28 (1 H, s, 4-H), 8.07 (1 H,
s, 8-H), 7.73 (2 H, d, J 7.9, 3Ј,5Ј-H), 7.61 (1 H, dd, J 8.9 and 7.4,
4Ј-H); m/z (HREIMS) 338.9797, 336.9819 (Mϩ, C14H6Cl2-
FN3O2 requires 338.9792, 336.9821).
(b) In HBF4–excess NaNO2. A stirred suspension of 5b
(1.55 g, 5.08 mmol) in 50% HBF4 (75 cm3) at Ϫ5 ЊC was
treated with solid NaNO2 (3.0 g, 43.5 mmol, added in small
portions over 5 h), then kept at Ϫ20 ЊC for 5 days. The resulting
mixture was neutralized with solid Na2CO3–ice, keeping the
temperature below Ϫ10 ЊC, and extracted with EtOAc
(4 × 150 cm3). The solvent was removed, then chromato-
graphy of the residue on silica gel, eluting with 1–2%
MeOH–CH2Cl2, gave firstly 3-(2,6-dichlorophenyl)-7-fluoro-
1,6-naphthyridin-2(1H)-one 19 (0.91 g, 58%), mp 254.5–
255.5 ЊC (from CH2Cl2–light petroleum) (Found: C, 54.0; H,
2.0; N, 9.2; F, 6.1. C14H7Cl2FN2O requires C, 54.4; H, 2.3; N,
9.1; F, 6.2%); δH([2H6]DMSO) 12.54 (1 H, br s, NH), 8.66
(1 H, s, 5-H), 8.13 (1 H, s, 4-H), 7.61 (2 H, d, J 8.2, 3Ј,5Ј-H),
7.49 (1 H, dd, J 8.8 and 7.4, 4Ј-H), 6.89 (1 H, s, 8-H);
δC([2H6]DMSO) 163.55 (d, JC-F 234, 7-C), 159.77 (s, 2-C),
148.95 (dd, JC-F 19, 5-C), 147.69 (d, JC-F 12, 8a-C), 138.13 (d,
4-C), 134.51 (2 C, s, 2Ј,6Ј-C), 133.51 (s, 1Ј-C), 130.85 (d, 4Ј-
C), 129.61 (d, JC-F 2.5, 3-C), 128.08 (2 C, d, 3Ј,5Ј-C), 114.34
(d, JC-F 2.5, 4a-C), 92.95 (dd, JC-F 42, 8-C).
Further elution of the column with 10–12% MeOH–CH2Cl2
gave
3-(2,6-dichlorophenyl)-1,6-naphthyridine-2,7(1H,6H)-
dione 20 (0.45 g, 29%), mp 363–369 ЊC (decomp.) (from
MeOH–CHCl3) (Found: C, 54.6; H, 2.5; N, 9.0. C14H8Cl2N2O2
requires C, 54.8; H, 2.6; N, 9.1%); δH([2H6]DMSO) 12.07, 11.55
(2 H, 2 br s, 2 × NH), 8.10 (1 H, s, 5-H), 7.67 (1 H, s, 4-H), 7.56
(2 H, d, J 8.1, 3Ј,5Ј-H), 7.44 (1 H, dd, J 8.8 and 7.5, 4Ј-H), 5.90
(1 H, s, 8-H); δC([2H6]DMSO) 161.84, 160.38 (2 s, 2,7-C), 147.87
(s, 8a-C), 139.65 (br d, 5-C), 138.60 (d, 4-C), 134.90 (2 C, s,
2Ј,6Ј-C), 133.90 (s, 1Ј-C), 130.50 (d, 4Ј-C), 127.97 (d, 2 C, 3Ј,5Ј-
C), 124.18 (s, 3-C), 105.09 (s, 4a-C), 95.50 (d, 8-C); m/z
(HRFABMS) 311.0015, 309.0042, 307.0067 (MHϩ, C14H9Cl2-
N2O2 requires 310.9982, 309.0012, 307.0041).
Further elution of the column with 0.25% MeOH–CH2Cl2
gave 18 (106 mg, 42%), and with 2–5% MeOH–CH2Cl2 gave 19
(92 mg, 36%).
(e) In HF–pyridine–limited NaNO2. A stirred suspension of
5b (99 mg, 0.325 mmol) in 65–70% HF–pyridine (2 cm3) at
0 ЊC was treated with solid NaNO2 (39 mg, 0.57 mmol), then
stirred at 0 ЊC for 30 min and then at 20 ЊC for 1 h. The
mixture was further treated with solid NaNO2 (11 mg, 0.16
mmol) at 0 ЊC, then stirred at 20 ЊC for 1 h. The resulting
mixture was cooled to 0 ЊC, neutralized with solid Na2CO3–
ice–water (keeping the temperature at or below 0 ЊC), then
diluted with water (to 150 cm3) and extracted with EtOAc
(3 × 100 cm3). The solvent was removed, then chromato-
graphy of the residue on silica gel, eluting with 0.5% MeOH–
CH2Cl2, gave 18 (75 mg, 75%).
(c) In HBF4–limited NaNO2. A stirred suspension of 5b (2.02
g, 6.62 mmol) in 50% HBF4 (80 cm3) at Ϫ5 ЊC was treated with
solid NaNO2 (0.50 g, 7.27 mmol, added in small portions over
4 h), then kept at Ϫ20 ЊC for 3 days. Further solid NaNO2
(0.25 g, 3.62 mmol, added in small portions over 4 h) was
added, then the mixture was kept at Ϫ20 ЊC for 2 days. The
resulting mixture was neutralized with solid Na2CO3–ice,
keeping the temperature below Ϫ10 ЊC, and extracted with
EtOAc (8 × 100 cm3). The solvent was removed, then chrom-
atography of the residue on silica gel, eluting with 1–1.5%
MeOH–CH2Cl2, gave firstly 3-(2,6-dichlorophenyl)-7-fluoro-
1,6-naphthyridin-2-amine 18 (1.12 g, 55%), mp 189–191 ЊC
(from CH2Cl2–light petroleum) (Found: C, 54.8; H, 2.3; N, 13.7;
F, 6.0. C14H8Cl2FN3 requires C, 54.6; H, 2.6; N, 13.6; F, 6.2%);
δH([2H6]DMSO) 8.67 (1 H, s, 5-H), 7.99 (1 H, s, 4-H), 7.64 (2 H,
d, J 8.1, 3Ј,5Ј-H), 7.51 (1 H, dd, J 8.8 and 7.4, 4Ј-H), 6.98 (1 H,
s, 8-H), 6.95 (2 H, br s, NH2); δC([2H6]DMSO) 163.81 (d, JC-F
231, 7-C), 158.67 (s, 2-C), 155.00 (d, JC-F 13, 8a-C), 149.53 (dd,
Diazotization of 3-(2,6-dichlorophenyl)-7-fluoro-1,6-
naphthyridin-2-amine 18
A stirred solution of 18 (106 mg, 0.344 mmol) in TFA (5 cm3) at
0 ЊC was treated with solid NaNO2 (64 mg, 0.93 mmol, added in
portions over 5 min), then stirred at 0 ЊC for 15 min, then at
20 ЊC for 2.5 h. The resulting mixture was added slowly to a
mixture of aqueous NaHCO3–Na2CO3 and ice (150 cm3) and
extracted with EtOAc (4 × 100 cm3). The solvent was removed,
then chromatography of the residue on silica gel, eluting with
1% MeOH–CH2Cl2, gave 19 (102 mg, 96%).
J. Chem. Soc., Perkin Trans. 1, 2000, 1843–1852
1849

View Article Online
Diazotization of 3-(3,5-dimethoxyphenyl)-1,6-naphthyridine-2,7-
diamine 5c
resulting mixture was neutralized with solid Na2CO3–ice, keep-
ing the temperature below Ϫ10 ЊC, diluted with water (to 150
cm3) and extracted with EtOAc (4 × 100 cm3). The solvent was
removed, then chromatography of the residue on silica gel, elut-
ing with 0–0.5% MeOH–CH2Cl2, gave firstly 2,7-difluoro-3-
(3,5-dimethoxyphenyl)-1,6-naphthyridine 31 (1.1 mg, 4%) as an
oil (see below).
(a) In HBF4–limited NaNO2. A stirred suspension of 5c (52
mg, 0.176 mmol) in 50% HBF4 (5 cm3) at Ϫ10 ЊC was treated
with solid NaNO2 (18 mg, 0.26 mmol, added in small portions
over 5 min), stirred at Ϫ10 ЊC for 3 h, and then kept at Ϫ20 ЊC
for 3 days. The resulting mixture was neutralized with solid
Na2CO3–ice, keeping the temperature below Ϫ5 ЊC, and
extracted with EtOAc (6 × 100 cm3). The solvent was removed,
then chromatography of the residue on silica gel, eluting with
1% MeOH–CH2Cl2, gave an oil (5 mg), which was further puri-
fied by preparative neutral alumina TLC (developed in 1%
EtOH/CHCl3). Two bands were recovered and each was eluted
with 5% MeOH–CH2Cl2. The less polar component was 3-(3,5-
dimethoxyphenyl)-7-fluoro-1,6-naphthyridin-2-amine 26 (1.5
mg, 3%), isolated as an oil (see below).
The more polar component (2.5 mg) was further purified by
preparative silica gel TLC (developed in 2% MeOH–CH2Cl2).
Recovery of the major band and elution with 6% MeOH–
CH2Cl2 gave3-(3,5-dimethoxy-2-nitrophenyl)-7-fluoro-1,6-naph-
thyridin-2-amine 27 (2.0 mg, 3%), mp 250–260 ЊC (decomp.)
(from MeOH–water); δH([2H6]DMSO) 8.64 (1 H, s, 5-H), 7.91
(1 H, s, 4-H), 7.00 (2 H, br s, NH2), 6.94 (1 H, s, 8-H), 6.92 (1 H,
d, J 2.4, 6Ј-H), 6.64 (1 H, d, J 2.4, 4Ј-H), 3.94, 3.88 (2 × 3 H, 2 s,
2 × OCH3); δC([2H6]DMSO) 163.82 (d, JC-F 232, 7-C), 161.89 (s,
5Ј-C), 159.08 (s, 2-C), 154.91 (d, JC-F 13, 8a-C), 153.03 (s, 3Ј-C),
149.64 (dd, JC-F 19, 5-C), 135.34 (d, 4-C), 134.38 (s, 1Ј-C),
131.70 (s, 2Ј-C), 120.66 (s, 3-C), 117.57 (s, 4a-C), 107.42 (d,
6Ј-C), 100.21 (d, 4Ј-C), 99.72 (dd, JC-F 36, 8-C), 56.85, 56.12
(2 q, 2 × OCH3); m/z (HRFABMS) 345.1011 (MHϩ, C16H14-
FN4O4 requires 345.0999).
Further elution with 0.5–1% MeOH–CH2Cl2 gave 3-(3,5-
dimethoxyphenyl)-7-fluoro-1,6-naphthyridin-2-amine 26 (21 mg,
81%), mp 225–227 ЊC (from CH2Cl2–hexane) (Found: C, 64.0;
H, 4.6; N, 14.1. C16H14FN3O2 requires C, 64.2; H, 4.7; N,
14.0%); δH([2H6]DMSO) 8.65 (1 H, s, 5-H), 8.00 (1 H, s, 4-H),
6.96 (1 H, s, 8-H), 6.90 (2 H, v br s, NH2), 6.64 (2 H, d, J 2.2,
2Ј,6Ј-H), 6.58 (1 H, t, J 2.2, 4Ј-H), 3.80 (6 H, s, 2 × OCH3);
δC([2H6]DMSO) 163.53 (d, JC-F 231, 7-C), 160.74 (2 C, s, 3Ј,5Ј-
C), 159.20 (s, 2-C), 154.32 (d, JC-F 13, 8a-C), 149.36 (dd, JC-F 19,
5-C), 138.30 (s, 1Ј-C), 135.39 (d, 4-C), 125.47 (d, JC-F 2, 3-C),
118.34 (d, JC-F 2, 4a-C), 106.53 (2 C, d, 2Ј,6Ј-C), 100.36 (d,
4Ј-C), 99.52 (dd, JC-F 36, 8-C), 55.21 (2 C, q, 2 × OCH3); m/z
(HREIMS) 299.1069 (Mϩ, C16H14FN3O2 requires 299.1070).
Further elution with 1–6% MeOH–CH2Cl2 gave minor
impurities, then elution with 6–12% MeOH–CH2Cl2 gave 2-
amino-3-(3,5-dimethoxyphenyl)-1,6-naphthyridin-7(6H)-one 30
(3.9 mg, 15%), mp 210–220 ЊC (decomp.) (from MeOH–
CH2Cl2–hexane); δH([2H6]DMSO) 11.50 (1 H, br s, NH), 8.23
(1 H, s, 5-H), 7.69 (1 H, s, 4-H), 6.77 (2 H, br s, NH2), 6.57 (2 H,
d, J 2.2, 2Ј,6Ј-H), 6.54 (1 H, t, J 2.1, 4Ј-H), 6.13 (1 H, s, 8-H),
3.78 (6 H, s, 2 × OCH3); δC([2H6]DMSO) 162.92 (s, 7-C), 160.66
(2 C, s, 3Ј,5Ј-C), 158.67 (s, 2-C), 154.10 (br s, 8a-C), 142.52 (br
d, 5-C), 138.51 (s, 1Ј-C), 136.15 (d, 4-C), 122.72 (s, 3-C), 111.22
(br s, 4a-C), 106.57 (2 C, d, 2Ј,6Ј-C), 100.46 (d, 8-C), 100.05 (d,
4Ј-C), 55.20 (2 C, q, 2 × OCH3); m/z (HREIMS) 297.1118 (Mϩ,
C16H15N3O3 requires 297.1113).
(b) In HBF4–excess NaNO2. A stirred suspension of 5c (1.00
g, 3.38 mmol) in 50% HBF4 (50 cm3) at Ϫ5 ЊC was treated with
solid NaNO2 (1.86 g, 27.0 mmol, added in small portions over
2 h), then kept at Ϫ20 ЊC for 4 days. The resulting mixture was
neutralized with solid Na2CO3–ice, keeping the temperature
below Ϫ5 ЊC, and extracted with EtOAc (6 × 150 cm3). The
solvent was removed, then chromatography of the residue on
silica gel, eluting with 1% MeOH–CH2Cl2, gave firstly quinone
imine 29 (48 mg, 4%), mp 290–296 ЊC (decomp.) (from MeOH–
CH2Cl2) (Found: C, 53.0; H, 2.2; N, 16.3; F, 5.3. C15H7FN4O5
requires C, 52.6; H, 2.1; N, 16.4; F, 5.6%); δH([2H6]DMSO)
9.57 (1 H, s, 5-H), 8.81 (1 H, s, 4-H), 7.70 (1 H, s, 8-H), 6.52
(1 H, s, 4Ј-H), 4.02 (s, 3 H, OCH3); δC([2H6]DMSO) 175.38 (s,
(d) Fresh HF–pyridine–pyridine–limited NaNO2. Freshly
opened (fuming) 65–70% HF–pyridine (8.66 cm3) was added
dropwise to dry pyridine (4.33 cm3) at 20 ЊC (water bath), with
rapid stirring, then 5c (328 mg, 1.11 mmol) was added, and the
mixture stirred at 20 ЊC for 15 min, then cooled to Ϫ10 ЊC.
Solid NaNO2 (116 mg, 1.68 mmol) was added in portions over
10 min, then the mixture was stirred at Ϫ10 ЊC for 30 min, and
then at 20 ЊC for 1.5 h. The mixture was further treated with
solid NaNO2 (116 mg, 1.68 mmol) at 0 ЊC, then stirred at 20 ЊC
for 2.5 h. The resulting mixture was cooled to Ϫ10 ЊC, neutral-
ized with solid Na2CO3–ice, keeping the temperature below
Ϫ5 ЊC, diluted with water (to 350 cm3) and extracted with
EtOAc (7 × 100 cm3). The solvent was removed, then chrom-
atography of the residue on silica gel, eluting with CH2Cl2, gave
firstly 2,7-difluoro-3-(3,5-dimethoxyphenyl)-1,6-naphthyridine
31 (59 mg, 18%), mp 154–157 ЊC (from CH2Cl2–hexane)
(Found: C, 63.9; H, 4.1; N, 9.3. C16H12F2N2O2 requires C, 63.6;
H, 4.0; N, 9.3%); δH([2H6]DMSO) 9.25 (1 H, s, 5-H), 8.97 (1 H,
d, JH-F 9.8, 4-H), 7.65 (1 H, s, 8-H), 6.87 (2 H, t, J 1.8, 2Ј,6Ј-H),
6.65 (1 H, t, J 2.2, 4Ј-H), 3.83 (6 H, s, 2 × OCH3); δC([2H6]-
DMSO) 163.52 (d, JC-F 213, 2- or 7-C), 161.11 (d, JC-F 227, 2- or
7-C), 160.53 (2 C, s, 3Ј,5Ј-C), 151.88 (dd, JC-F 18, 5-C), 150.89
(dd, JC-F 21 and 13, 8a-C), 141.67 (dd, JC-F 8, 4-C), 134.51 (d,
JC-F 4, 1Ј-C), 124.30 (dd, JC-F 33 and 3, 3-C), 121.89 (d, JC-F 2,
4a-C), 107.17 (2 C, dd, JC-F 2, 2Ј,6Ј-C), 103.12 (dd, JC-F 37, 8-C),
100.63 (d, 4Ј-C), 55.36 (2 C, q, 2 × OCH3); m/z (HREIMS)
302.0868 (Mϩ, C16H12F2N2O2 requires 302.0867).
C᎐O), 165.06 (d, J
239, 7-C), 160.49, 158.91 (2 s, 2,2Ј-C),
᎐
C-F
155.36 (dd, JC-F 18, 5-C), 152.93 (d, JC-F 13, 8a-C), 143.36 (s,
3Ј-C), 138.49 (s, 6Ј-C), 138.43 (d, 4-C), 121.46, 114.74, 107.15
(3 s, 1Ј,3,4a-C), 106.01 (d, 4Ј-C), 102.70 (dd, JC-F 37, 8-C),
57.72 (q, OCH3); m/z (HRFABMS) 343.0481 (MHϩ, C15H8F-
N4O5 requires 343.0479).
Further elution with 1% MeOH–CH2Cl2 gave a mixture, then
elution with 2% MeOH–CH2Cl2 gave quinone 28 (38 mg, 4%),
mp 265–275 ЊC (decomp.) (from MeOH–CH2Cl2); δH([2H6]-
DMSO) 12.48 (1 H, br s, NH), 8.66 (1 H, s, 5-H), 8.16 (1 H, s,
4-H), 6.98 (1 H, d, J 2.4, 6Ј-H), 6.84 (1 H, s, 8-H), 6.21 (1 H, d,
J 2.4, 4Ј-H), 3.84 (3 H, s, OCH3); δC([2H6]DMSO) 187.04 (s,
5Ј-C), 179.45 (s, 2Ј-C), 163.67 (d, JC-F 234, 7-C), 160.21, 158.89
(2 s, 2,3Ј-C), 149.40 (dd, JC-F 19, 5-C), 147.65 (d, JC-F 13, 8a-C),
140.46 (s, 1Ј-C), 138.38 (d, 4-C), 134.73 (d, 6Ј-C), 125.96 (d, JC-F
2.8, 3-C), 114.29 (d, JC-F 2.8, 4a-C), 107.41 (d, 4Ј-C), 92.87 (dd,
JC-F 42, 8-C), 56.62 (q, OCH3); m/z (HREIMS) 300.0567 (Mϩ,
C15H9FN2O4 requires 300.0546).
Further elution with 1% MeOH–CH2Cl2 gave 26 (257 mg,
78%).
Further elution with 1–1.5% MeOH–CH2Cl2 gave 3-(3,5-
dimethoxyphenyl)-7-fluoro-1,6-naphthyridin-2(1H)-one 32 (6
mg, 2%), mp 266–270 ЊC (from MeOH–CH2Cl2–hexane)
(Found: C, 64.0; H, 4.4; N, 9.3. C16H13FN2O3 requires C, 64.0;
H, 4.4; N, 9.3%); δH([2H6]DMSO) 12.31 (1 H, br s, NH), 8.62
(1 H, s, 5-H), 8.24 (1 H, s, 4-H), 6.90 (2 H, d, J 2.3, 2Ј,6Ј-H),
6.83 (1 H, s, 8-H), 6.55 (1 H, t, J 2.2, 4Ј-H), 3.79 (6 H, s,
(c) HF–pyridine–limited NaNO2. A stirred suspension of 5c
(25.7 mg, 86.8 µmol) in 65–70% HF–pyridine (1 cm3) at Ϫ5 ЊC
was treated with solid NaNO2 (9.3 mg, 135 µmol), then stirred
at Ϫ5 ЊC for 2 h. The mixture was further treated with solid
NaNO2 (3.2 mg, 46 µmol) and stirred at Ϫ5 ЊC for 2 h. The
1850
J. Chem. Soc., Perkin Trans. 1, 2000, 1843–1852

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2 × OCH3); δC([2H6]DMSO) 163.16 (d, JC-F 233, 7-C), 161.00 (s,
2-C), 159.98 (2 C, s, 3Ј,5Ј-C), 148.61 (dd, JC-F 19, 5-C), 146.94
(d, JC-F 12, 8a-C), 137.08 (s, 1Ј-C), 135.17 (d, 4-C), 131.58 (d,
JC-F 3, 3-C), 115.00 (d, JC-F 3, 4a-C), 106.80 (2 C, d, 2Ј,6Ј-C),
100.04 (d, 4Ј-C), 92.29 (dd, JC-F 42, 8-C), 55.19 (2 C, q,
2 × OCH3); m/z (HREIMS) 300.0907 (Mϩ, C16H13FN2O3
requires 300.0910).
8-C), 55.82 (t, NCH2), 54.77, 52.73 (2 × 2 C, 2 t, 2 × N(CH2)2),
45.74 (q, NCH3), 40.11 (t, NCH2), 26.00 (t, CH2).
Further elution of this column with 5–10% MeOH–CH2Cl2
containing 0.75–1% conc. NH4OH gave material which was
treated with aqueous Na2CO3 (50 cm3) and extracted with
CH2Cl2 (5 × 50 cm3) to give 2,7-bis{[3-(4-methylpiperazin-1-
yl)propyl]amino}-3-phenyl-1,6-naphthyridine 33 (121 mg, 60%)
as a foam (Found: C, 66.3; H, 8.5; N, 20.3. C30H44N8ؒ1.5H2O
requires C, 66.3; H, 8.7; N, 20.6%); δH([2H6]DMSO) 8.41 (1 H, s,
5-H), 7.54 (1 H, s, 4-H), 7.49 (2 H, t, J 7.3, 3Ј,5Ј-H), 7.44 (2 H,
d, J 6.9, 2Ј,6Ј-H), 7.41 (1 H, t, J 7.1, 4Ј-H), 6.39 (1 H, br t, J 5.7,
NHCH2), 6.25 (1 H, s, 8-H), 6.17 (1 H, br t, J 5.5, NHCH2),
3.47 (2 H, td, J 6.5 and 5.7, NHCH2), 3.23 (2 H, td, J 6.6 and
6.1, NHCH2), 2.6–2.0 (16 H, br s, 2 × N(CH2)4N), 2.36 (2 H, t,
J 6.9, NCH2), 2.29 (2 H, t, J 6.6, NCH2), 2.15, 2.09 (2 × 3 H, 2 s,
2 × NCH3), 1.71 (2 H, quintet, J 7.0, CH2), 1.69 (2 H, quintet,
J 6.8, CH2); δC([2H6]DMSO) 159.16, 156.46 (2 s, 2,7-C), 152.55
(s, 8a-C), 150.01 (d, 5-C), 137.34 (s, 1Ј-C), 135.20 (d, 4-C),
128.98, 128.71 (2 × 2 C, 2 d, 2Ј,3Ј,5Ј,6Ј-C), 127.66 (d, 4Ј-C),
121.52 (s, 3-C), 112.84 (s, 4a-C), 94.43 (d, 8-C), 56.07, 55.60
(2 t, 2 × NCH2), 54.73, 54.35, 52.68, 52.65 (4 × 2 C, 4 t, 4 ×
N(CH2)2), 45.66, 45.51 (2 q, 2 × NCH3), 39.98, 39.68 (2 t,
2 × NCH2), 26.03, 25.27 (2 t, 2 × CH2); m/z (HRFABMS)
517.3752 (MHϩ, C30H45N8 requires 517.3767).
Diazotization of 3-(3,5-dimethoxyphenyl)-7-fluoro-1,6-
naphthyridin-2-amine 26
A stirred solution of 26 (2.8 mg, 9.36 µmol) in TFA (1.0 cm3) at
0 ЊC was treated with solid NaNO2 (1.5 mg, 21.7 µmol), then
stirred at 0 ЊC for 2.5 h. The resulting mixture was added drop-
wise to a mixture of aqueous NaHCO3–Na2CO3 and ice (60
cm3) and extracted with EtOAc (3 × 50 cm3). The solvent was
removed, then the residue was purified by preparative silica gel
TLC (developed twice in 2% MeOH–CH2Cl2). Recovery of the
major band and elution with 8% MeOH–CH2Cl2 gave 27 (0.9
mg, 28%).
Hydrolysis of 2,7-difluoro-3-(3,5-dimethoxyphenyl)-1,6-
naphthyridine 31
(a) In NaOH–THF–water. A solution of 31 (20.4 mg, 67.6
µmol) in THF (1.8 cm3) was treated with NaOH (0.16 g, 4.0
mmol) and water (0.2 cm3), then the mixture was stirred at
53 ЊC for 3 days. The resulting suspension was diluted with
aqueous NaHCO3 (50 cm3) and extracted with CH2Cl2 (4 × 50
cm3) and EtOAc (3 × 50 cm3). The solvents were removed, then
chromatography of the residue on silica gel, eluting with 1%
MeOH–CH2Cl2, gave 32 (20 mg, 99%).
Reaction of 7-chloro-3-(2,6-dichlorophenyl)-1,6-naphthyridin-2-
amine 13b with 1-(3-aminopropyl)-4-methylpiperazine
A mixture of 13b (40 mg, 0.12 mmol) and 1-(3-aminopropyl)-4-
methylpiperazine (1.0 g, 6.37 mmol) under nitrogen was stirred
at 160 ЊC for 3 days. The resulting mixture was diluted with
aqueous Na2CO3 (50 cm3) and extracted with EtOAc (5 × 50
cm3). The solvent was removed, then chromatography of the
residue on alumina, eluting with 0.75–1% MeOH–CH2Cl2, gave
a crude solid (39 mg), which was further purified by chrom-
atography on silica gel. Elution with 7–10% MeOH–CH2Cl2
containing 0.2% Et3N gave material which was treated with
aqueous Na2CO3 (50 cm3) and extracted with EtOAc (3 × 50
cm3) to give 3-(2,6-dichlorophenyl)-7-{[3-(4-methylpiperazin-1-
yl)propyl]amino}-1,6-naphthyridin-2-amine 35 (24 mg, 44%),
mp 152–154 ЊC (from CH2Cl2–light petroleum) (Found: C,
59.3; H, 6.2; N, 18.5. C22H26Cl2N6 requires C, 59.3; H, 5.8; N,
18.9%); δH([2H6]DMSO) 8.44 (1 H, s, 5-H), 7.59 (2 H, d, J 8.0,
3Ј,5Ј-H), 7.58 (1 H, s, 4-H), 7.46 (1 H, dd, J 8.7 and 7.5, 4Ј-H),
6.50 (1 H, br t, J 5.6, NHCH2), 6.23 (2 H, br s, NH2), 6.19 (1 H,
s, 8-H), 3.23 (2 H, q, J 6.4, NHCH2), 2.6–2.0 (8 H, br s,
N(CH2)4N), 2.37 (2 H, t, J 7.1, NCH2), 2.15 (3 H, s, NCH3),
1.71 (2 H, quintet, J 7.0, CH2); δC([2H6]DMSO) 159.26, 157.70
(2 s, 2,7-C), 153.28 (s, 8a-C), 150.37 (d, 5-C), 136.92 (d, 4-C),
135.28 (2 C, s, 2Ј,6Ј-C), 134.55 (s, 1Ј-C), 130.61 (d, 4Ј-C), 128.49
(2 C, d, 3Ј,5Ј-C), 116.12, 112.62 (2 s, 3,4a-C), 93.76 (d, 8-C),
55.74 (t, NCH2), 54.72, 52.69 (2 × 2 C, 2 t, 2 × N(CH2)2), 45.68
(q, NCH3), 40.01 (t, NCH2), 25.95 (t, CH2).
(b) In HF–pyridine–pyridine–water. A suspension of 31 (10.4
mg, 34.4 µmol) in a premixed solution of fresh (fuming) 65–
70% HF–pyridine (1.66 cm3) and dry pyridine (0.83 cm3) (pre-
pared as described in (d) above) was treated with water (0.10
cm3), then the mixture was stirred at 20 ЊC for 2 days. The
resulting mixture was cooled to Ϫ10 ЊC, neutralized with solid
Na2CO3–ice, keeping the temperature below Ϫ5 ЊC, diluted
with water (to 50 cm3) and extracted with CH2Cl2 (5 × 50 cm3)
and EtOAc (3 × 50 cm3). The solvents were removed, then
chromatography of the residue on silica gel, eluting with
CH2Cl2, gave firstly recovered 31 (4.7 mg, 45%). Further elution
with 1% MeOH–CH2Cl2 gave 32 (5.6 mg, 54%).
Reaction of 7-chloro-3-phenyl-1,6-naphthyridin-2-amine 13a
with 1-(3-aminopropyl)-4-methylpiperazine
A mixture of 13a (100 mg, 0.39 mmol) and 1-(3-aminopropyl)-
4-methylpiperazine (1.0 g, 6.37 mmol) was stirred at 160 ЊC for
5 days. The resulting mixture was diluted with aqueous Na2CO3
(50 cm3) and extracted with EtOAc (7 × 50 cm3). The solvent
was removed, then chromatography of the residue on alumina,
eluting with 0.7% MeOH–CH2Cl2, gave a crude oil (161 mg),
which was further purified by chromatography on silica gel.
Elution with 4–5% MeOH–CH2Cl2 containing 0.5–0.75%
conc. NH4OH gave material which was treated with aqueous
Na2CO3 (50 cm3) and extracted with CH2Cl2 (5 × 50 cm3) to
give 7-{[3-(4-methylpiperazin-1-yl)propyl]amino}-3-phenyl-1,6-
naphthyridin-2-amine 34 (11 mg, 7.5%), mp 152–155 ЊC (from
CH2Cl2–hexane) (Found: C, 69.8; H, 7.5; N, 22.1. C22H28N6
requires C, 70.2; H, 7.5; N, 22.3%); δH([2H6]DMSO) 8.46 (1 H, s,
5-H), 7.65 (1 H, s, 4-H), 7.48 (4 H, m, 2Ј,3Ј,5Ј,6Ј-H), 7.40 (1 H,
m, 4Ј-H), 6.47 (1 H, br t, J 5.7, NHCH2), 6.21 (2 H, br s, NH2),
6.19 (1 H, s, 8-H), 3.23 (2 H, td, J 6.6 and 6.0, NHCH2), 2.6–2.0
(8 H, br s, N(CH2)4N), 2.36 (2 H, t, J 7.1, NCH2), 2.15 (3 H, s,
NCH3), 1.71 (2 H, quintet, J 6.9, CH2); δC([2H6]DMSO) 159.08,
158.33 (2 s, 2,7-C), 152.66 (s, 8a-C), 150.40 (d, 5-C), 137.63 (s,
1Ј-C), 136.09 (d, 4-C), 128.93, 128.63 (2 × 2 C, 2 d, 2Ј,3Ј,5Ј,6Ј-
C), 127.55 (d, 4Ј-C), 120.81 (s, 3-C), 113.46 (s, 4a-C), 93.85 (d,
Reaction of 3-(2,6-dichlorophenyl)-7-fluoro-1,6-naphthyridin-2-
amine 18 with 1-(3-aminopropyl)-4-methylpiperazine
A solution of 18 (266 mg, 0.86 mmol) and 1-(3-aminopropyl)-4-
methylpiperazine (1.37 g, 8.73 mmol) in 2-ethoxyethanol (20
cm3) under nitrogen was stirred at reflux for 5 d. The solvent
was removed under reduced pressure, then the residue was
diluted with aqueous Na2CO3 (100 cm3) and extracted with
EtOAc (3 × 120 cm3). The solvent was removed, then chrom-
atography of the residue on silica gel, eluting with 0.5–1%
MeOH–CH2Cl2, gave firstly recovered 18 (25 mg, 9%). Further
elution with 10% MeOH–CH2Cl2 gave a crude solid (44 mg),
which was further purified by chromatography on alumina,
eluting with 0.5% MeOH–CH2Cl2, to give 3-(2,6-dichloro-
phenyl)-7-(4-methylpiperazin-1-yl)-1,6-naphthyridin-2-amine
36 (21 mg, 6%), mp 223–227 ЊC (from CH2Cl2–light petroleum)
(Found: C, 58.5; H, 5.1; N, 17.8. C19H19Cl2N5 requires C, 58.8;
J. Chem. Soc., Perkin Trans. 1, 2000, 1843–1852
1851

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H, 4.9; N, 18.0%); δH([2H6]DMSO) 8.56 (1 H, s, 5-H), 7.67 (1 H,
s, 4-H), 7.60 (2 H, d, J 8.0, 3Ј,5Ј-H), 7.47 (1 H, dd, J 8.7 and 7.6,
4Ј-H), 6.51 (1 H, s, 8-H), 6.34 (2 H, br s, NH2), 3.53 (4 H, t,
J 4.8, N(CH2)2), 2.44 (4 H, t, J 4.8, N(CH2)2), 2.24 (3 H, s,
NCH3); δC([2H6]DMSO) 159.32, 157.86 (2 s, 2,7-C), 153.50 (s,
8a-C), 149.73 (d, 5-C), 136.72 (d, 4-C), 135.16 (2 C, s, 2Ј,6Ј-C),
134.34 (s, 1Ј-C), 130.73 (d, 4Ј-C), 128.52 (2 C, d, 3Ј,5Ј-C),
117.41, 113.11 (2 s, 3,4a-C), 96.28 (d, 8-C), 54.26 (2 C, t,
N(CH2)2), 45.74 (q, NCH3), 45.00 (2 C, t, N(CH2)2); m/z
(HREIMS) 389.0983, 387.1001 (Mϩ, C19H19Cl2N5 requires
389.0988, 387.1018).
DMSO) 11.65 (1 H, br s, NH), 8.37 (1 H, s, 5-H), 7.71 (1 H, s,
4-H), 7.55 (2 H, d, J 7.9, 3Ј,5Ј-H), 7.42 (1 H, dd, J 8.7 and 7.6,
4Ј-H), 7.11 (1 H, br t, J 5.5, NHCH2), 6.15 (1 H, s, 8-H), 3.26
(2 H, q, J 6.2, NHCH2), 2.6–2.0 (8 H, br s, N(CH2)4N), 2.34
(2 H, t, J 7.1, NCH2), 2.15 (3 H, s, NCH3), 1.69 (2 H, quintet,
J 7.0, CH2); δC([2H6]DMSO) 160.52, 159.61 (2 s, 2,7-C), 150.00
(d, 5-C), 145.37 (s, 8a-C), 139.02 (d, 4-C), 135.11 (2 C, s, 2Ј,6Ј-
C), 134.72 (s, 1Ј-C), 130.19 (d, 4Ј-C), 127.94 (2 C, d, 3Ј,5Ј-C),
123.26 (s, 3-C), 108.08 (s, 4a-C), 87.33 (br d, 8-C), 55.57 (t,
NCH2), 54.72, 52.68 (2 × 2 C, 2 t, N(CH2)4N), 45.70 (q, NCH3),
39.51 (t, NCH2), 26.01 (t, CH2).
Further elution of the first column with 11–14% MeOH–
CH2Cl2 gave a mixture, then elution with 15% MeOH–CH2Cl2
containing 1% Et3N gave material which was treated with
aqueous Na2CO3 (50 cm3) and extracted with EtOAc (3 × 50
cm3) to give 35 (177 mg, 46%).
3-(2,6-Dichlorophenyl)-7-(4-methylpiperazin-1-yl)-1,6-
naphthyridin-2-amine 36
A solution of 18 (83 mg, 0.27 mmol) and 1-methylpiperazine
(1.50 cm3, 13.5 mmol) in pentan-2-ol (10 cm3) was stirred at
reflux for 4 days. Further 1-methylpiperazine (1.20 cm3, 10.8
mmol) was added and the mixture stirred at reflux for 3 days.
The solvent was removed under reduced pressure, then the
residue was diluted with aqueous Na2CO3 (50 cm3) and
extracted with EtOAc (4 × 50 cm3). The solvent was removed,
then chromatography of the residue on alumina, eluting with
0.4% MeOH–CH2Cl2, gave 36 (82 mg, 78%).
Reaction of 3-(3,5-dimethoxyphenyl)-7-fluoro-1,6-naphthyridin-
2-amine 26 with 1-(3-aminopropyl)-4-methylpiperazine
A solution of 26 (108 mg, 0.36 mmol) and 1-(3-aminopropyl)-4-
methylpiperazine (0.573 g, 3.65 mmol) in 2-ethoxyethanol (10
cm3) under nitrogen was stirred at reflux for 5 days. Further
1-(3-aminopropyl)-4-methylpiperazine (1.72 g, 11.0 mmol) was
added, and the mixture stirred under nitrogen at reflux for 5 days.
The solvent was removed under reduced pressure, then the resi-
due was diluted with aqueous Na2CO3 (50 cm3) and extracted
with EtOAc (5 × 50 cm3). The solvent was removed, then
chromatography of the residue on silica gel, eluting with 0.5%
MeOH–CH2Cl2, gave firstly recovered 26 (5.5 mg, 5%). Further
elution with 1–4% MeOH–CH2Cl2 containing 0.5% conc.
NH4OH gave a mixture, then further elution with 4–8%
MeOH–CH2Cl2 containing 0.5–0.75% conc. NH4OH gave
material which was treated with aqueous Na2CO3 (50 cm3)
and extracted with CH2Cl2 (4 × 50 cm3) to give 3-(3,5-dimeth-
oxyphenyl)-7-{[3-(4-methylpiperazin-1-yl)propyl]amino}-1,6-
naphthyridin-2-amine 37 (68 mg, 43%), mp 120–124.5 ЊC (from
CH2Cl2–hexane) (Found: C, 61.9; H, 7.1; N, 17.8.
C24H32N6O2ؒ1.5H2O requires C, 62.2; H, 7.6; N, 18.1%);
δH([2H6]DMSO) 8.45 (1 H, s, 5-H), 7.67 (1 H, s, 4-H), 6.59 (2 H,
d, J 2.2, 2Ј,6Ј-H), 6.52 (1 H, t, J 2.1, 4Ј-H), 6.46 (1 H, br t, J 5.5,
NHCH2), 6.27 (2 H, br s, NH2), 6.18 (1 H, s, 8-H), 3.79 (6 H,
s, 2 × OCH3), 3.23 (2 H, m, NHCH2), 2.6–2.1 (8 H, br s,
N(CH2)4N), 2.36 (2 H, t, J 7.0, NCH2), 2.15 (3 H, s, NCH3),
1.70 (2 H, quintet, J 6.9, CH2); δC([2H6]DMSO) 160.65 (2 C, s,
3Ј,5Ј-C), 159.01, 158.11 (2 s, 2,7-C), 152.64 (s, 8a-C), 150.35 (d,
5-C), 139.53 (s, 1Ј-C), 135.78 (d, 4-C), 120.64 (s, 3-C), 113.23 (s,
4a-C), 106.49 (2 C, d, 2Ј,6Ј-C), 99.70 (d, 4Ј-C), 93.82 (d, 8-C),
55.79 (t, NCH2), 55.17 (2 C, q, 2 × OCH3), 54.76, 52.72 (2 ×
2 C, 2 t, 2 × N(CH2)2), 45.71 (q, NCH3), 39.94 (t, NCH2), 25.98
(t, CH2).
Acknowledgements
This work was partially supported by the Auckland Division of
the Cancer Society of New Zealand.
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A solution of 19 (95 mg, 0.31 mmol) and 1-(3-aminopropyl)-4-
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