Novel derivatives of the benzo[b][1,6]napthyridine system

Article abstract of DOI:10.1002/jhet.5570430222

An efficient synthesis of 2-hydroxy-6-methylbenzo[b][1,6]naphthyridin-1(2H) -one was devised. The hydroxy group was alkylated, acylated and replaced by hydrogen. Electrophilic nitration, bromination and chlorosulfonation occurred readily in the 4-position

Full text of DOI:10.1002/jhet.5570430222

Mar-Apr 2006
405
Novel Derivatives of the Benzo[b][1,6]naphthyridine System
Leslie W. Deady* and Michael L. Rogers
Chemistry Department, La Trobe University, Victoria 3086, Australia
Received July 27, 2005
An efficient synthesis of 2-hydroxy-6-methylbenzo[b][1,6]naphthyridin-1(2H)-one was devised. The
hydroxy group was alkylated, acylated and replaced by hydrogen. Electrophilic nitration, bromination and
chlorosulfonation occurred readily in the 4-position. From the last, various sulfonamide derivatives were
prepared. A selection of the products was screened by the National Cancer Institute. Cytotoxicities were
generally low.
J. Heterocyclic Chem., 43, 405 (2006).
Compound 1 was reported as a product from reaction of
Vilsmeier reagent with the appropriate quinoline analogue
of homophthalic acid [1]. We subsequently found that 1
reacted readily with a variety of amines to give 2, precur-
sors to a new series of potential antitumor carboxamides
(Scheme 1) [2]. Analogues of 1 react in the same way [3].
The change from 1 to 2 clearly involves ring opening
and ring closing, but details of timing of the various steps
has not been established. The only intermediate isolated is
3 (Figure 1), where this very insoluble first product precip-
itated from the reaction mixture, but this says nothing
about how the later ring interconversion occurs.
Scheme 1
Figure 1
3+
example, a deep red colour with Fe , but this aspect has
not yet been investigated.
Formation of 4a.
Compound 1 was reacted with 2.2 equivalents of hydrox-
ylamine hydrochloride and excess triethylamine in N,N-
dimethylformamide (DMF) at room temperature for 16
hours. In the reaction of 1 with most amines, the insoluble
product 2 precipitates from the reaction mixture within a
short time. But, with hydroxylamine, the precipitated solid
was a water soluble triethylamine salt of 2a along with tri-
ethylamine hydrochloride. If aqueous sodium hydroxide
was added and the solution then acidified, 2a was precipi-
tated (64%). However, if the reaction mixture was heated at
100° for 1 hour before evaporation of the volatiles and
addition of water to the residue, 4a was obtained as a filter-
(i) Excess RNH /DMF/20° OR 1.1 mol RNH /excess NEt /DMF/20°.
2
2
3
The standard conditions generally give high yields of 2
but, during further studies on the scope of the change from
1 to 2, we have found that hydroxylamine provides an
interesting case where a simple change in reaction condi-
tions can provide a high proportion of 2a (2 with R=OH)
or the decarboxylated compound 4a (Scheme 2). This
access to 4a prompted us to investigate the chemistry of
this novel system, and this paper reports on the preparation
of various derivatives, some of which have been screened
for anticancer activity. Compounds containing a 2-hydroxy
substituent, such as 4a, are metal chelators forming, for
1
able solid (79%). The H nmr spectrum was characteristic
in that the singlet for H-3 in 2a (8.6 ppm) was replaced by a
set of doublets at 7.9 (H-3) and 6.7 (H-4) ppm in 4a; the

406
L. W. Deady and M. L. Rogers
Vol. 43
Scheme 3
upfield doublet was a useful diagnostic feature as it could
be seen in the spectra of complex mixtures.
Both hydroxylamine and the N-OH function appear to
be important in favoring the formation of the decarboxy-
lated product, though it is not evident why this should be
so. The pathway summarized in Scheme 2 reflects the
overall result though it does not explain the complexities.
Thus, 2a is stable when heated as a solid, or as a solution in
DMF (with or without triethylamine), but the addition of
1.2 equivalents of hydroxylamine gives efficient conver-
sion to 4a. Also, 2b (2 with R=butyl) was significantly less
reactive under the same conditions (DMF/triethylamine/
hydroxylamine/heat) and the result was more complicated.
Five equivalents of hydroxylamine were required to pro-
duce appreciable reaction. After 16 hours at 100°, about
40% of 4b (R=butyl) was formed, the rest being 2b and
unidentified minor byproducts. One can postulate that a
Scheme 2
(i) excess MeI/excess K CO /DMF/100°/3 h. (ii) 2 mol Cl(CH )
2 3
2
3
NMe .HCl/excess K CO /DMF/100°/16 h. (iii) Ac O/AcOH/60°/1 h.
2
2
3
2
(iv) 2.5 mol p-TsCl/excess NEt /DMF/20°/6 h. (v) MeNO /reflux/5 h.¸
3
2
ditions with 3-(dimethylamino)propyl chloride, but for a
longer time, gave the analogous 9. Conventional acetylation
with acetic anhydride/acetic acid at 60° gave the acetoxy
compound 10. Tosylation to 11 was achieved with tosyl chlo-
ride, at room temperature in DMF containing triethylamine.
In accord with literature reports of the behaviour of N-tosy-
loxyisocarbostyryl [5], 11 when refluxed in nitromethane for
5 hours underwent a clean rearrangement to the 4-tosyloxy
isomer 12. Interestingly, 14, the 4-bromo analogue of 11 (pre-
pared from 13—below and Scheme 4), underwent the same
reaction, with loss of the bromo group, to give the same 12.
Other Reactions at the 4-Position.
(i) 1.2 mol NH OH•HCl/NEt /DMF/20°/16 h. (ii) 2.2 mol NH OH•HCl/
2
3
2
The 2-hydroxy (4a), 2-methoxy (8) and 2-acetoxy (10)
compounds were potential substrates but most reactions
were done on 8. It has been noted that N-methylisoquino-
lin-1-one readily undergoes electrophilic substitution reac-
tions at the 4-position [6,7], and similar reactivity was seen
with the present compounds.
NEt /DMF/20°/16 h, then 100°/1 h.
3
ring opened species like 5 is formed, both in the initial
reaction from 1 and also from the product 2a, and decar-
boxylation, where it occurs, does so from this α,β-unsatu-
rated acid prior to ring closure to 4a.
4-Acetylisochromandione (6) (Figure 1) was reported to
undergo this type of rearrangement, with decarboxylation,
when heated with hydroxylamine hydrochloride in pyri-
dine, to give 7 [4].
Bromination.
Molecular bromine reacted readily without the need for
a catalyst. Thus, 4a with bromine in hot 1,4-dioxane gave
the 4-bromo compound 13 within 1 minute, while 8 was
reacted similarly in benzene to give 15 (Scheme 4); the ini-
tial precipitate in each case was the corresponding hydro-
bromide salt. Substitution in the 4- rather than 3-position
Reactions of the 2-Hydroxy Function.
Alkylation, acylation and sulfonylation were easily
achieved (Scheme 3). Thus, reaction at 100° with
iodomethane in DMF containing solid potassium carbonate
gave the methoxy compound 8, and reaction under these con-
was confirmed by an HMBC nmr experiment on 13 where
3
J
coupling was seen between H-3 and the two quater-
CH
nary carbons C-1 and C-4a.

Mar-Apr 2006
Novel Derivatives of the Benzo[b][1,6]naphthyridine System
407
Scheme 4
(i) Br /1,4-dioxane/reflux/1 min. (ii) 2.5 mol p-TsCl/excess NEt /DMF/20°/1 h. (iii) excess Br /C H /reflux/10 min. (iv) excess
2
3
2
6 6
Br /CH Cl /–10°/10 min. (v) heat >170°. (vi) 1.2 mol NBS/cat. Bz O /C H /reflux/50 min. (vii) 1 mol Hg (NO ) •2H O/(MeOCH ) /
2
2
2
2
2
6
6
2
3 2
2
2 2
reflux/1 h. (viii) 10 mol NEt /(MeOCH ) /reflux/4 h. (ix) Ceased reflux of viii and added 50 mol AcOH /5 mol solid NaClO /vigorous stir
3
2 2
2
20°/16 h. (x) 2.5 mol CDI/1,4-dioxane/reflux/16 h. Recharge with 2.5 mol CDI/reflux/8 h. (xi) NH (CH ) NMe /CH Cl /20°/16 h.
2
2 2
2
2
2
We have evidence that the bromination reaction follows
an addition-elimination pathway. Thus, when bromine was
added to a solution of 8 in deuteriochloroform in an nmr
tube, the development of two doublets at 6.3 and 5.7 ppm
(J = 2.5 Hz) could be seen, consistent with intermediacy of
16, though the spectrum was not clean. When this solution
was heated, these signals diminished and the low field sin-
glet for H-10 of 15 appeared.
dichloromethane and it was necessary to carry out a wash
with dilute carbonate and water before isolating a clean
product. All data for this were consistent with the bromo-
hydroxy compound 17 and it was stable to recrystallization
from acetonitrile. When the solid was heated above its
melting point, a clean change to 15 occurred. The forma-
tion of a bromo-hydroxy addition compound has previ-
ously been reported from a somewhat related reaction of
an N-methylisoquinolinone [6].
On a preparative scale, the reaction was done at –10° in
Scheme 5
(i) AcONO /Ac O/50°/30 min. (ii) ClSO H/70°/16 h. (iii) SOCl /DMF/reflux/45 min. (iv) 10% K CO /
2
2
3
2
2
3
+
20°/8 h, then H . (v) amine/NEt /CH Cl /N /<4°/30 min, then 20°/16 h.
3
2
2
2

408
L. W. Deady and M. L. Rogers
Vol. 43
Scheme 6
Compound 8 was also reacted with N-bromosuccinimide
(NBS)/benzoyl peroxide in refluxing benzene. It was evi-
dent that in these conditions also, the 4-position was the
most reactive but the overall product was not as clean as
when 15, preformed as above, was subjected to NBS
bromination and the bromomethyl compound 18 was pro-
duced. This compound was then converted in a sequence
we have developed [8], through nitrate ester 19 to acid 21
(Scheme 4). Finally, this was converted to the carboxam-
ide 22, an analogue of a series whose antitumor activity we
have previously reported [2].
Nitration.
Neither 4a nor 10 was successfully nitrated but 8 reacted
readily with acetyl nitrate under mild conditions to give a
59% yield of 23 (Scheme 5) (reaction with potassium
nitrate/concentrated sulfuric acid was not as clean and also
gave probable nitration in the benzo ring).
Chlorosulfonation.
(i) ClSO H/70°/5 h. (ii) SOCl /DMF/reflux/45 min. (iii) amine/NEt /
3
2
3
CH Cl /N /<4°/30 min, then 20°/16 h. (iv) 1 mol morpholine/1 mol
2
2
2
Reaction of the 2-methoxy compound (8) with chloro-
sulfonic acid at 70° for 16 hours gave, on addition to ice, a
mixture of 4-sulfonyl chloride (24) and 4-sulfonic acid
(25) as their hydrochloride salts (Scheme 5). Similar
behaviour has been reported for chlorosulfonation of some
quinolines and isoquinolines [9]. Reaction under more
forcing conditions failed to eliminate the acid, but this was
achieved by treating the above mixture with hot thionyl
chloride and DMF, and the free base 24 was obtained by
careful treatment with dilute potassium carbonate. A sam-
ple of the sulfonic acid 25 was obtained by mild alkaline
hydrolysis of the hydrochloride of 24.
The reaction of 4a with chlorosulfonic acid under the
above conditions was similar but in this case the sulfonic
acid 26 was the sole isolated product (Scheme 6). When
this was treated with thionyl chloride/DMF, not only was
the sulfonyl chloride formed but the functionalities at the
1- and 2-positions were also affected and the fully aro-
matic 27 was formed. The crude product was sufficiently
pure for direct use in further reactions.
NEt /CH Cl /N /–18°/16 h.
3
2
2
2
The product was a mixture but chromatography provided
samples of one monosubstituted compound, assigned as
35, along with, surprisingly, an appreciable but variable
amount of the disubstituted compound 28. This was not a
viable source of 35 and an alternative synthesis, which also
confirmed the above assignment, is described below.
With only the sulfonyl chloride present in 24, reaction
with a selection of amines, as above, gave the sulfon-
amides 30–34.
Further transformations were carried out on 30 (Scheme
7). Since, as described above, the 2-hydroxy group of 26
did not survive thionyl chloride treatment, the 2-hydroxy
sulfonamide 36 was prepared by demethylation of 30 in
refluxing acetic acid/aqueous hydrobromic acid. It has
Scheme 7
Further Reactions of the Sulfonyl Chlorides.
The sulfonamide class of drugs has diverse pharmaco-
logical activities [10] and the ready synthesis of 24 and 27
prompted us to synthesize some sulfonamide and related
derivatives for anticancer testing.
When 27 was reacted with an excess of an amine in
dichloromethane at room temperature [11], both chlorines
were displaced and the sulfonamides 28 and 29 were
formed (Scheme 6).
The potential of 27 as an intermediate would be
enhanced if the chlorines could be replaced by two differ-
ent amines. To this end, we looked at reaction with one
equivalent of morpholine but the result was disappointing.
(i) 40% HBr/HOAc/130°/16 h. (ii) PhCH NCO/K CO /acetone/reflux/16 h.
2
2
3

Mar-Apr 2006
Novel Derivatives of the Benzo[b][1,6]naphthyridine System
409
been stated that conversion of N-methoxyamides to N-
hydroxyamides is more difficult to achieve than demethy-
lation of phenol methyl ethers [12]. But, in the present
case, the reaction occurred quite readily; the reflux time
was important since overreaction resulted in the replace-
ment of the N-OH by NH. It was therefore necessary to
stop the reaction with some 30 still present and to separate
this from 36 by chromatography.
In a different type of reaction, an example of a sulfony-
lurea 37 was prepared by reacting 30 with benzyliso-
cyanate in refluxing acetone containing solid potassium
carbonate. These literature conditions [13] were more suc-
cessful than the use of triethylamine/acetone or aqueous
base.
With the problems encountered in trying to control the
direction of monosubstitution in the dichloro compound 27
(above), an alternative approach was investigated. We
found that reactions of N-OMe compounds with solid
potassium hydroxide in hot DMF brought about a clean
conversion to the NH analogues without otherwise affect-
ing the tricycle or substituents. Thus, neither the 4-bromo
(15 →38—Scheme 8) nor sulfonamide (33→39) was
affected. It has been reported that the strong, sterically hin-
dered base, lithium diisopropylamide achieved the
phosphoryl chloride gave 35 (and thereby confirmed this
as the product from mono-morpholine substitution in 27,
Scheme 6) and we used benzylamine to illustrate the ready
displacement of the chlorine to form 40.
Biological Activity.
Our prime interest is in anticancer agents; testing for
biological activity in this potentially interesting set has
been limited to this area and compounds 4a, 9, 12, 22, 25,
28, 30, 32, 33, 36, 37 were submitted to the National
Cancer Institute, USA. Of these, only 9 and 22 satisfied the
prescreen toxicity criteria. A particular point of interest is
that the sulfonamide 32 is a direct analogue of a carboxam-
ide that shows potent in vitro cytotoxicity [3]. In the full
assay for cytotoxicity against 60 human cancer cell lines,
both 9 [most active GI [15], 3.4 µM (SN12C renal can-
50
cer); MGM [16], 28.2 µM] and 22 [most active GI , 0.68
50
µM (HCC-2998 colon cancer); MGM, 4.0 µM] showed
unexceptional activity. The result for 22 indicates that the
positioning of the carboxamide on the chromophore is cru-
cial, since we have reported other benzonaphthyridinone
carboxamides as potent antitumor agents [2,3].
EXPERIMENTAL
demethoxylation of N-methoxyamides by an E elimina-
2
1
13
H Nuclear Magnetic Resonance (nmr) spectra and C nmr
tion of formaldehyde [14]. Presumably a similar mecha-
nism is involved in the present case; the N-OH compound
4a was unaffected by these conditions.
The ability to use this route to control the identity of the
amine moiety in 1,4-disubstituted compounds was now
demonstrated by further reactions of 39. Reaction with
spectra were recorded at 300.13 MHz and 75.47 MHz, respec-
tively, on a Bruker Avance 300 spectrometer. Chemical shifts are
reported as delta values (δ) in parts per million relative to tetram-
ethylsilane. Standard PENDANT, HSQC, HMBC and COSY
spectra were used to make proton and carbon assignments.
Melting points were recorded on a Reichert “Thermopan” micro-
scope hot stage apparatus and are uncorrected. Electrospray mass
spectra (esms) were recorded by Mr C. Verdon, La Trobe
University, on a VG BioQ triple quadrupole mass spectrometer
using positive ion mode with acetonitrile–water (1:1) containing
1% formic acid as mobile phase; unless otherwise stated, the
cone voltage was 50 V. High resolution mass spectra (hrms) were
recorded at the University of Tasmania, Australia, using liquid
secondary ionisation mode with 3-nitrobenzyl alcohol as liquid
matrix. Microanalyses were performed at the Campbell
Microanalytical Laboratory, University of Otago, New Zealand.
Commercial reagents were used without further purification.
Silica gel (silica gel 60, 230–400 mesh ASTM) and preparative
Scheme 8
layer chromatography (plc) plates (20 × 20 cm, silica gel 60 F
,
254
2 mm) were supplied by Merck Chemicals. Unless otherwise
stated, the eluent used for flash chromatography was ethyl
acetate–hexane (1:1).
4-[(Dimethylamino)methylene]-6-methyl-4H-pyrano[4,3-
b]quinoline-1,3-dione (1).
The previously reported method [1] was slightly modified: To
N,N-dimethylformamide (16 mL) at 0° (salt-ice bath) was added
phosphoryl chloride (3.2 mL), dropwise, with constant stirring.
Ethyl (3-carboxy-8-methylquinolin-2-yl)acetate (3.17 g, 12.05
mmol) was added, the salt-ice bath was removed, and stirring
was continued for a further 2 hours. The reaction mixture was fil-
tered and washed with a little cold dichloromethane to afford 1 as
(i) KOH/DMF/100°/30 min. (ii) POCl /reflux/8 h.
3
(iii) PhCH NH /NEt /CH Cl /N /20°/16 h.
2
2
3
2
2
2

410
L. W. Deady and M. L. Rogers
Vol. 43
an orange solid (2.93 g, 86%), with mp and nmr data as previ-
ously reported.
umn was washed with acetone and the product was eluted with
acetone–methanol–triethylamine (100:5:1) (R , 0.2). The O-alky-
f
2-Hydroxy-6-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naph-
thyridine-4-carboxylic acid (2a) [3] and 2-butyl-6-methyl-1-oxo-
1,2-dihydrobenzo[b][1,6]naphthyridine-4-carboxylic acid (2b)
[2] were prepared as previously reported.
lated derivative 9 was thus obtained as a lemon coloured solid
(0.26 g, 47%), mp 75–78° [petroleum spirit (bp 80–110°)]; H
1
nmr (deuteriochloroform): δ 1.95 (quintet, J = 6.8 Hz, 2H,
CH CH CH ), 2.24 [s, 6H, N(CH ) ], 2.51 [18] (t, J = 7.2 Hz,
2
2
2
3 2
2H, CH CH CH ), 2.76 (s, 3H, ArCH ), 4.32 (t, J = 6.4 Hz, 2H,
2
2
2
3
2-Hydroxy-6-methylbenzo[b][1,6]naphthyridin-1(2H)-one (4a).
CH CH CH ), 6.75 (d, J = 8.1 Hz, 1H, H-4), 7.37 (t, J = 7.6 Hz,
2
2
2
To a stirred suspension of the dione 1 (3.45 g, 12.23 mmol) in
N,N-dimethylformamide (60 mL) was added triethylamine (15
mL), followed by hydroxylamine hydrochloride (1.89 g, 27.22
mmol). The whole was stirred for 16 hours at room temperature,
and then the mixture was heated at 100° for 1 hour, during which
time dissolution occurred. The volatiles were removed under
reduced pressure, water was added, and the red solid was filtered
and washed with water to give 4a (2.18 g, 79%), which was used
directly in further reactions. Recrystallization from ethanol gave
4a as mustard coloured needles, mp 252–254°. A solution in
1H, H-8), 7.48 (d, J = 8.1 Hz, 1H, H-3), 7.59 (d, J = 6.8 Hz, 1H,
H-7), 7.75 (d, J = 8.3 Hz, 1H, H-9), 9.14 (s, 1H, H-10); C nmr
13
(deuteriochloroform): δ 17.7 (ArCH ), 25.8 (CH CH CH ), 45.0
3
2
2
2
[N(CH ) ], 55.5 (CH CH CH ), 75.0 (CH CH CH ), 107.5 (C-
3 2
2
2
2
2
2
2
4), 120.7 (C-10a), 125.7 (C-9a), 126.0 (C-8), 126.7 (C-9), 131.7
(C-7), 133.3 (C-3), 136.6 (C-6), 137.8 (C-10), 149.6 (C-5a),
150.0 (C-4a), 158.4 (C-1).
Anal. Calcd. for C H N O : C, 69.43; H, 6.80; N, 13.49.
18 21
3 2
Found: C, 69.27; H, 6.54; N, 13.48.
2-Acetoxy-6-methylbenzo[b][1,6]naphthyridin-1(2H)-one (10).
3+
1
ethanol gave a deep red coloration upon the addition of Fe ; H
nmr (dimethyl sulfoxide-d ): δ 2.73 (s, 3H, ArCH ), 6.73 (d, J =
The N-hydroxy compound 4a (0.50 g, 2.21 mmol), acetic
anhydride (15 mL) and acetic acid (3 mL) were heated at 60° for
1 hour. Dissolution occurred slowly during this time, and the
resultant solution was poured onto ice (150 mL). The initially-
formed oil solidified after stirring for 1 hour, and the solid was
filtered and washed with water to give 10 as a pale yellow solid
(0.48 g, 81%). A sample for analysis was heated to above its
melting point and, after being cooled, was purified by flash col-
6
3
7.9 Hz, 1H, H-4), 7.51 (t, J = 7.5 Hz, 1H, H-8), 7.74 (d, J = 6.8
Hz, 1H, H-7), 7.88 (d, J = 8.0 Hz, 1H, H-3), 8.06 (d, J = 8.3 Hz,
1H, H-9), 9.28 (s, 1H, H-10), 11.61 (br s, 1H, OH—exchanged
13
with added deuterium oxide); C nmr (dimethyl sulfoxide-d ): δ
6
17.9 (ArCH ), 105.8 (C-4), 120.4 (C-10a), 125.7 (C-9a), 126.2
3
(C-8), 127.6 (C-9), 132.1 (C-7), 136.0 (C-6), 136.1 (C-3), 137.8
(C-10), 149.3 (C-5a), 150.2 (C-4a), 158.2 (C-1).
Anal. Calcd. for C H N O : C, 69.02; H, 4.46; N, 12.38.
Found: C, 68.70; H, 4.41; N, 12.42.
umn chromatography (R , 0.5) to give a pale yellow solid, mp
13 10
2 2
f
1
178–186°; H nmr (deuteriochloroform): δ 2.42 (s, 3H, COCH ),
3
2.83 (s, 3H, ArCH ), 6.88 [17] (d, J = 8.1 Hz, 1H, H-4), 7.34 (d,
3
2-Methoxy-6-methylbenzo[b][1,6]naphthyridin-1(2H)-one (8).
J = 8.1 Hz, 1H, H-3), 7.46 (t, J = 7.6 Hz, 1H, H-8), 7.68 (d, J = 6.9
Hz, 1H, H-7), 7.83 (d, J = 8.3 Hz, 1H, H-9), 9.21 (s, 1H, H-10);
The N-hydroxy compound 4a (2.72 g, 12.04 mmol), potassium
carbonate (2.72 g, 19.68 mmol), iodomethane (3 mL, 48.19
mmol), and N,N-dimethylformamide (60 mL) were combined,
and the whole was heated at 100° for 3 hours. The reaction mix-
ture was stripped of solvent under reduced pressure, ice-water
was added, and the solid was collected by filtration and washed
with water to furnish 8 (2.49 g, 86%) as bronze flakes, mp
13
C nmr (deuteriochloroform): δ 17.6 (COCH ), 17.8 (ArCH ),
3
3
107.6 (C-4), 120.4 (C-10a), 125.8 (C-9a), 126.4 (C-8), 126.8 (C-
9), 132.2 (C-7), 132.5 (C-3), 136.7 (C-6), 138.5 (C-10), 149.6 (C-
5a), 150.0 (C-4a), 157.2 (C-1), 166.6 (COCH ).
3
Anal. Calcd. for C H N O : C, 67.16; H, 4.51; N, 10.44.
15 12
2 3
Found: C, 67.29; H, 4.65; N, 10.52.
1
212–214° (methanol); H nmr (deuteriochloroform): δ 2.83 (s,
2-(4-Tosyloxy)-6-methylbenzo[b][1,6]naphthyridin-1(2H)-one
(11).
3H, ArCH ), 4.13 (s, 3H, OCH ), 6.85 [17] (d, J = 8.1 Hz, 1H, H-
3
3
4), 7.46 (dd, J = 8.0, 7.3 Hz, 1H, H-8), 7.53 (d, J = 8.0 Hz, 1H, H-
3), 7.68 (d, J = 6.8 Hz, 1H, H-7), 7.84 (d, J = 8.2 Hz, 1H, H-9),
To a suspension of the N-hydroxy compound 4a (0.30 g, 1.33
mmol) in N,N-dimethylformamide (15 mL) and triethylamine (1
mL) was added, in one portion, 4-toluenesulfonyl chloride (0.63
g, 3.30 mmol) and the whole was stirred for 6 hours. The reaction
was filtered to remove a small amount of insoluble material, ice-
water was added (ca 100 mL), and the resultant solid was col-
lected by filtration and washed with water to give the N-tosyloxy
compound 11 as a yellow solid (0.30 g, 59%). Recrystallization
resulted in some rearrangement to the 4-tosyloxy derivative 12
(below). Therefore, the solid was dissolved in a small amount of
dichloromethane, the solution was filtered, and the product was
reprecipitated by the addition of petroleum spirit (bp 80–110°)
13
9.25 (s, 1H, H-10); C nmr (deuteriochloroform): δ 17.9
(ArCH ), 64.2 (OCH ), 107.4 (C-4), 120.8 (C-10a), 125.7 (C-
3
3
9a), 126.2 (C-8), 126.8 (C-9), 132.1 (C-7), 132.9 (C-3), 136.4 (C-
6), 138.3 (C-10), 149.2 (C-5a), 149.9 (C-4a), 158.1 (C-1).
Anal. Calcd. for C H N O : C, 69.99; H, 5.03; N, 11.66.
14 12
2 2
Found: C, 70.03; H, 4.89; N, 11.61.
2-[3-(Dimethylamino)propoxy]-6-methylbenzo[b][1,6]naph-
thyridin-1(2H)-one (9).
The N-hydroxy compound 4a (0.40 g, 1.77 mmol), 3-
(dimethylamino)propyl chloride hydrochloride (0.56 g, 3.54
mmol) and potassium carbonate (1.12 g) in N,N-dimethylfor-
mamide (35 mL) were heated at 100° for 16 hours. The volatiles
were removed under reduced pressure, water was added, and the
product was extracted with dichloromethane (× 3). The organic
fraction was washed with brine (× 3), dried over magnesium sul-
fate, filtered and the filtrate was evaporated under reduced pres-
sure to leave the crude product as a brown oil that solidified (0.40
g). This was purified by flash column chromatography; the col-
1
and had mp 131–135°; H nmr (dimethyl sulfoxide-d ): δ 2.42 (s,
6
3H, ArCH -4′), 2.72 (s, 3H, ArCH -6), 6.75 (d, J = 8.3 Hz, 1H,
3
3
H-4), 7.48 (d, J = 8.0 Hz, 2H, H-3′, H-5′), 7.55 (t, J = 7.6 Hz, 1H,
H-8), 7.73 (d, J = 8.3 Hz, 1H, H-3), 7.79 (d, J = 6.7 Hz, 1H, H-7),
7.88 (d, J = 8.0 Hz, 2H, H-2′, H-6′), 8.06 (d, J = 8.2 Hz, 1H, H-9),
13
9.17 (s, 1H, H-10); C nmr (dimethyl sulfoxide-d ): δ 17.8
6
(ArCH -6), 21.4 (ArCH -4′), 107.7 (C-4), 120.3 (C-10a), 125.8
(C-9a), 126.9 (C-8), 127.7 (C-9), 129.5 (C-2′, C-6′), 129.8 (C-1′),
3
3

Mar-Apr 2006
Novel Derivatives of the Benzo[b][1,6]naphthyridine System
411
130.6 (C-3′, C-5′), 132.9 (C-7), 135.2 (C-3), 136.2 (C-6), 138.9
(C-10), 147.5 (C-4′), 149.4 (C-5a), 149.9 (C-4a), 157.1 (C-1).
Anal. Calcd. for C H N O S: C, 63.15; H, 4.24; N, 7.36.
7.76 (d, J = 7.0 Hz, 1H, H-7), 7.82 (d, J = 8.2 Hz, 1H, H-9), 7.89 (s,
1H, H-3), 7.92 (d, J = 8.3 Hz, 2H, H-2′, H-6′), 9.06 (s, 1H, H-10);
13
C nmr (deuteriochloroform): δ 17.4 (ArCH -6), 21.6 (ArCH -4′),
3
3
20 16
2 4
102.2 (C), 119.4 (C), 126.0 (C-9a), 126.4 (C-9), 127.3 (C-8), 129.4
(C-2′, C-6′), 129.8 (C-3′, C-5′), 129.9 (C-1′), 132.6 (C-7), 133.6 (C-
3), 137.7 (C-6), 139.1 (C-10), 146.0 (C-4a), 147.0 (C-4′), 149.5 (C-
Found: C, 62.90; H, 4.13; N, 7.49.
6-Methyl-4-(4-tosyloxy)benzo[b][1,6]naphthyridin-1(2H)-one
(12).
+
5a), 156.9 (C-1); esms (36 V): m/z 461.5, 459.5; both (M+H) .
The N-tosyloxy compound 11 (0.15 g, 0.39 mmol) and
nitromethane (20 mL) were heated under reflux for ca 5 hours [as
4-Bromo-2-methoxy-6-methylbenzo[b][1,6]naphthyridin-1(2H)-
one (15).
monitored by tlc—ethyl acetate–hexane (3:7); R 11, 0.7; R 12,
f
f
To a stirred solution of the N-methoxy compound 8 (1.00 g,
4.16 mmol) in hot benzene (50 mL) was added bromine (1 mL,
19.41 mmol), and the resultant suspension was stirred for 10 min-
utes. The reaction mixture was filtered and the orange solid was
washed with diethyl ether. This material (1.84 g) was partitioned
between 10% potassium carbonate and dichloromethane, and the
organic layer was washed twice more with base, then with water
(× 3), dried over magnesium sulfate, filtered, and the filtrate was
evaporated under reduced pressure to give the monobromo com-
pound 15 (0.94 g, 71%) as an orange solid, mp 180–189° (gradu-
0.2]. The solvent was evaporated under reduced pressure to leave
the 4-tosyloxy compound 12 (0.15 g, 100%) as a brown solid with
1
mp 253–256° (ethanol × 2); H nmr (dimethyl sulfoxide-d ): δ
6
2.22 (s, 3H, ArCH -4′), 2.57 (s, 3H, ArCH -6), 7.30 (d, J = 8.0
3
3
Hz, 2H, H-3′, H-5′), 7.45–7.53 (d + t, 2H, H-3, H-8—collapsed to
s + d with added deuterium oxide), 7.73 (d, J = 6.7 Hz, 1H, H-7),
7.81 (d, J = 8.0 Hz, 2H, H-2′, H-6′), 8.01 (d, J = 8.2 Hz, 1H, H-9),
9.14 (s, 1H, H-10), 11.41 (d, J = 6.0 Hz, 1H, NH—exchanged with
13
added deuterium oxide); C nmr (dimethyl sulfoxide-d ): δ 17.4
6
(ArCH -6), 21.1 (ArCH -4′), 120.0 (C-10a), 126.1 (C-9a), 126.7
3
3
1
ally formed needles) (acetonitrile); H nmr (deuteriochloroform):
(C-8), 127.5 (C-9), 127.8 (C-3), 128.5 (C-2′, C-6′), 128.7 (C-4),
129.9 (C-3′, C-5′), 132.3 (C-1′), 132.5 (C-7), 136.3 (C-6), 138.5
(C-10), 145.5 (C-4′), 145.9 (C-4a), 148.7 (C-5a), 161.4 (C-1).
δ 2.91 (s, 3H, ArCH ), 4.14 (s, 3H, OCH ), 7.53 (t, J = 7.6 Hz,
3
3
1H, H-8), 7.75 (d, J = 6.9 Hz, 1H, H-7), 7.87–7.90 (m, 2H, H-9,
13
H-3), 9.27 (s, 1H, H-10); C nmr (deuteriochloroform): δ 17.4
Anal. Calcd. for C H N O S: C, 63.15; H, 4.24; N, 7.36.
20 16
2 4
(ArCH ), 64.6 (OCH ), 101.2 (C), 120.0 (C), 125.9 (C-9a), 126.4
Found: C, 63.12; H, 4.15; N, 7.59.
3
3
(C-9), 126.9 (C-8), 132.1 (C-7), 132.9 (C-3), 137.5 (C-6), 138.4
(C-10), 146.1 (C-4a), 149.3 (C-5a), 157.6 (C-1).
4-Bromo-2-hydroxy-6-methylbenzo[b][1,6]naphthyridin-1(2H)-
one (13).
Anal. Calcd. for C H BrN O : C, 52.69; H, 3.47; N, 8.78.
14 11
2 2
To the N-hydroxy compound 4a (0.40 g, 1.77 mmol) dissolved
in boiling 1,4-dioxane (60 mL) was added bromine (1 mL, 19.41
mmol), and the whole was heated under reflux for 1 minute. The
reaction mixture was cooled, filtered, and the orange solid was
washed with diethyl ether. This material was suspended in ethanol
(100 mL) and triethylamine (5 mL) (with initial sonication to
obtain homogeneity), and the mixture was evaporated to dryness
under reduced pressure. Water was added, and the solid was col-
lected by filtration and washed with water, to give 13 as a pale yel-
low solid (0.47 g, 87%), mp >300°. A sample was recrystallized
from n-propanol for analysis but retained ca 10% solvent even
after drying at 150° and ca 0.01 mmHg for 24 hours. A solution in
Found: C, 52.93; H, 3.53; N, 8.78.
4-Bromo-3-hydroxy-2-methoxy-6-methyl-3,4-dihydrobenzo[b]-
[1,6]naphthyridin-1(2H)-one (17).
To the N-methoxy compound 8 (0.40 g, 1.66 mmol) dissolved
in dichloromethane (40 mL) at ca –10° (acetone-ice bath) was
added an excess of bromine (0.5 mL, 9.70 mmol) in one portion,
and the whole was stirred at the same temperature for 10 minutes.
The resultant suspension was diluted with more dichloromethane
and was washed with ice-10% sodium carbonate (× 4, or until the
organic phase was yellow) and then with ice-water. The organic
fraction was dried over magnesium sulfate, filtered and the fil-
trate was concentrated to ca 5 mL under reduced pressure with-
out heating. The resultant white solid was collected by filtration
and washed with a small amount of cold dichloromethane to ren-
der the alcohol 17 as a white powder (0.36 g, 64%), mp 159–162°
(acetonitrile). The white powder turned light pink over a few
3+
1
ethanol gave a deep red coloration upon the addition of Fe ; H
nmr (dimethyl sulfoxide-d ): δ 2.79 (s, 3H, ArCH ), 7.58 (t, J =
6
3
6.8 Hz, 1H, H-8), 7.82 (d, J = 5.9 Hz, 1H, H-7), 8.13 (d, J = 7.6
Hz, 1H, H-9), 8.43 (s, 1H, H-3), 9.33 (s, 1H, H-10), 11.83 (s, 1H,
13
OH); C nmr (dimethyl sulfoxide-d ): δ 17.5 (ArCH ), 98.7 (C),
6
3
1
days and red on long standing; H nmr (dimethyl sulfoxide-d ): δ
119.9 (C), 125.9 (C-9a), 127.0 (C-8), 127.3 (C-9), 132.5 (C-7),
136.3 (C-6), 136.4 (C-3), 138.5 (C-10), 146.3 (C-4a), 148.7 (C-
5a), 157.9 (C-1); esms: m/z 307.2, 305.2; both (M+H) .
6
2.70 (s, 3H, ArCH ), 3.86 (s, 3H, OCH ), 5.51 (d, J = 2.4 Hz, 1H,
3
3
+
H-4), 5.60 (dd, J = 5.3, 2.5 Hz, 1H, H-3—collapsed to d, J = 2.5
Hz, with added deuterium oxide), 7.49 (d, J = 5.3 Hz, 1H, OH—
exchanged with added deuterium oxide), 7.59 (t, J = 7.6 Hz, 1H,
H-8), 7.77 (d, J = 7.0 Hz, 1H, H-7), 8.04 (d, J = 8.1 Hz, 1H, H-9),
Anal. Calcd. for C H BrN O •0.1 C H O: C, 51.34; H, 3.17;
13
9
2
2
3 8
N, 9.00. Found: C, 51.72; H, 2.98; N, 9.22.
4-Bromo-2-(4-tosyloxy)-6-methylbenzo[b][1,6]naphthyridin-
1(2H)-one (14).
13
8.99 (s, 1H, H-10); C nmr (dimethyl sulfoxide-d ): δ 17.6
6
(ArCH ), 49.4 (C-4), 62.1 (OCH ), 85.0 (C-3), 120.6 (C-10a),
3
3
127.1 (C-9a), 127.5 (C-9), 127.9 (C-8), 132.5 (C-7), 136.4 (C-6),
138.3 (C-10), 147.4 (C-5a), 152.8 (C-4a), 159.1 (C-1).
From the bromo compound 13 (0.47 g, 1.54 mmol), as for the
tosyloxy compound 11, except with a greater volume of N,N-
dimethylformamide (50 mL) and the reaction was carried out for 1
hour. The bromo-N-tosyloxy compound 14 (0.50 g, 71%) was
obtained as an off white solid with mp 103–107°; the solid turned
Anal. Calcd. for C H BrN O : C, 49.87; H, 3.89; N, 8.31.
14 13
2 3
Found: C, 50.13; H, 3.97; N, 8.45.
The dichloromethane filtrate contained primarily a mixture of
more 17 (R , 0.5) and the monobromo compound 15 (R , 0.7).
1
orange and began degrading upon standing for 1 week [19]; H nmr
f
f
(deuteriochloroform): δ 2.47 (s, 3H, ArCH -4′), 2.90 (s, 3H, ArCH -
Compound 17 (0.36 g, 1.07 mmol) was heated to above its
melting point, then cooled, and the resultant brown solid was dis-
3
3
6), 7.37 (d, J = 8.3 Hz, 2H, H-3′, H-5′), 7.53 (t, J = 7.6 Hz, 1H, H-8),

412
L. W. Deady and M. L. Rogers
Vol. 43
solved in dichloromethane and washed with 10% sodium bicar-
bonate and then with brine (× 3). The organic phase was dried
over magnesium sulfate, filtered and evaporated under reduced
pressure to give the monobromo compound 15 as an orange solid
(0.24 g, 70%) with mp and nmr data as above.
or (b), the resultant dark solution was taken off reflux and,
while still hot, acetic acid (5 mL) was added, followed by the
immediate addition of sodium chlorite (tech. grade, 80%) (0.95 g,
8.40 mmol). The yellow suspension was stirred vigorously
overnight, and then the solid collected by filtration and washed
with a little acetone to give a mixture of the title compound as its
triethylamine salt and triethylamine hydrochloride. This mixture
was suspended in water (10 mL) containing 3% hydrochloric
acid (3 mL), and the yellow free acid 21 was collected by filtra-
tion and washed with water (0.26 g, 45%). It was used in this
state in the next step. A recrystallized sample from 1,4-dioxane
4-Bromo-2-methoxy-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyri-
dine-6-carboxaldehyde (20) or 4-Bromo-2-methoxy-1-oxo-1,2-
dihydrobenzo[b][1,6]naphthyridine-6-carboxylic Acid (21).
To the bromo-N-methoxy compound 15 (0.82 g, 2.57 mmol)
dissolved in hot benzene (82 mL) was added N-bromosuccin-
imide (0.55 g, 3.09 mmol) and benzoyl peroxide (0.06 g, 0.25
mmol), and the whole was heated under reflux for 50 minutes.
The resultant solution was cooled, washed with cold 10% potas-
sium carbonate (× 2) and then with brine (× 3). The organic frac-
tion was dried over magnesium sulfate, filtered and the solvent
was removed under reduced pressure to give 4-bromo-6-(bro-
momethyl)-2-methoxybenzo[b][1,6]naphthyridin-1(2H)-one
(18) as an orange solid (1.13 g), sufficiently pure for further reac-
tion. A sample recrystallized from diisopropyl ether–
1
had mp 292–295° (dec.) (after darkening >285°); H nmr
(dimethyl sulfoxide-d ): δ 4.05 (s, 3H, OCH ), 7.92 (t, J = 7.8
6
3
Hz, 1H, H-8), 8.68 (d, J = 8.2 Hz, 1H, H-7), 8.78 (d, J = 7.3 Hz,
1H, H-9), 8.87 (s, 1H, H-3), 9.68 (s, 1H, H-10), 16.04 (s, 1H,
13
COOH); C nmr (dimethyl sulfoxide-d , 100°): δ 65.1 (OCH ),
6
3
96.2 (C), 121.6 (C), 124.2 (C-6), 126.4 (C-9a), 127.5 (C-8), 135.1
(C-7), 138.2 (C-9), 138.5 (C-3), 141.7 (C-10), 146.8 (C-5a),
147.4 (C-4a), 156.5 (C-1), 165.5 (COOH).
4-Bromo-N-[2-(dimethylamino)ethyl]-2-methoxy-1-oxo-1,2-
dihydrobenzo[b][1,6]naphthyridine-6-carboxamide (22).
1
dichloromethane had mp 223–225°; H nmr (deuteriochloro-
form): δ 4.14 (s, 3H, OCH ), 5.34 (s, 2H, CH Br), 7.61 (dd, J =
3
2
A suspension of the acid 21 (0.25 g, 0.72 mmol) and 1,1′-car-
bonyldiimidazole (CDI) (0.29 g, 1.79 mmol) in 1,4-dioxane (20
mL) was heated under reflux for 16 hours. The reaction was
recharged with the same amount of CDI, and reflux was contin-
ued for a further 8 hours. The volatiles were removed under
reduced pressure and a solution of N,N-dimethylethylenediamine
(0.5 mL, 4.55 mmol) in dichloromethane (25 mL) was added, and
the solution was left stirring overnight. The solution was diluted
with more dichloromethane, and washed once with 10% sodium
hydroxide and then with brine (× 3). The organic layer was dried
over magnesium sulfate, filtered and the filtrate was evaporated
under reduced pressure to leave the crude target (0.34 g). This
solid was recrystallized from acetonitrile to render the carboxam-
8.3, 7.1 Hz, 1H, H-8), 7.94 (s, 1H, H-3), 8.01–8.05 (m, 2H, H-9,
13
H-7), 9.31 (s, 1H, H-10); C nmr (deuteriochloroform): δ 28.5
(CH Br), 64.6 (OCH ), 101.1 (C), 120.8 (C), 126.1 (C-9a), 127.0
2
3
(C-8), 129.3 (C-9), 133.4 (C-7), 133.6 (C-3), 136.3 (C-6), 138.8
(C-10), 146.9 (C-4a), 147.7 (C-5a), 157.5 (C-1).
To a solution of crude 18 (0.78 g, 1.97 mmol) in hot 1,2-
dimethoxyethane (35 mL) was added mercury (I) nitrate dihydrate
(MW 561.2, 1.11 g, 1.97 mmol), and the whole was heated under
reflux for 1 hour. While still warm, the suspension was filtered
twice under suction and the filtrate was poured onto ice. The
resultant solid was collected by filtration and washed with water
to give 4-bromo-2-methoxy-1-oxo-1,2-dihydrobenzo[b][1,6]-
naphthyridine-6-methanol nitrate (19) as a yellow solid (0.65 g,
95% from 15) with mp 193–195°, which was used in this state in
1
ide 22 as a light brown solid (0.16 g, 53%), mp 179–181°; H
1
further reactions; H nmr (deuteriochloroform): δ 4.15 (s, 3H,
nmr (deuteriochloroform): δ 2.38 [s, 6H, N(CH ) ], 2.78 (t, J =
3 2
OCH ), 6.30 (s, 2H, CH ONO ), 7.66 (dd, J = 8.2, 7.2 Hz, 1H, H-
6.8 Hz, 2H, CH CH NMe ), 3.83 (q, J = 6.5 Hz, 2H,
3
2
2
2
2
2
8), 7.94–7.98 (m, 2H, H-3, H-7), 8.10 (d, J = 8.4 Hz, 1H, H-9),
CH CH NMe ), 4.15 (s, 3H, OCH ), 7.74 (t, J = 7.7 Hz, 1H, H-
2
2
2
3
13
9.34 (s, 1H, H-10); C nmr (deuteriochloroform): δ 64.7 (OCH ),
8), 7.97 (s, 1H, H-3), 8.13 (dd, J = 8.3, 1.3 Hz, 1H, H-9), 9.00 (dd,
3
70.4 (CH ONO ), 100.7 (C), 120.8 (C), 125.9 (C-9a), 126.7 (C-
J = 7.4, 1.1 Hz, 1H, H-7), 9.30 (s, 1H, H-10), 11.34 (br s, 1H,
2
2
13
8), 130.0 (C-9), 130.7 (C-6), 132.6 (C-7), 133.9 (C-3), 138.9 (C-
10), 147.2 (C-4a), 147.9 (C-5a), 157.4 (C-1).
CONH); C nmr (deuteriochloroform): δ 37.6 (CH CH NMe ),
2
2
2
45.0 [N(CH ) ], 58.3 (CH CH NMe ), 64.8 (OCH ), 99.4 (C),
3 2
2
2
2
3
To the nitrate ester 19 (0.63 g, 1.66 mmol) in 1,2-
dimethoxyethane (60 mL) was added triethylamine (1.70 g, 16.80
mmol), and the whole was heated under reflux for 4 hours. Then,
either:
120.1 (C), 126.2 (C-9a), 127.1 (C-8), 128.2 (C-6), 132.6 (C-9),
134.8 (C-3), 137.5 (C-7), 140.0 (C-10), 146.7 (C-4a), 147.2 (C-
5a), 156.9 (C-1), 164.7 (CONH).
Anal. Calcd. for C H BrN O •0.5H O: C, 50.48; H, 4.71; N,
18 19
4
3
2
(a) the volatiles were removed under reduced pressure, ice-
water was added, and the resultant solid was collected by filtra-
tion and washed with water to furnish the aldehyde 20 as a light
brown solid (0.49 g, 89%), mp 248–250° (dec.) (N,N-dimethyl-
13.08. Found: C, 50.42; H, 4.48; N, 13.03.
2-Methoxy-6-methyl-4-nitrobenzo[b][1,6]naphthyridin-1(2H)-
one (23).
1
formamide as yellow needles); H nmr (dimethyl sulfoxide-d ): δ
To acetic anhydride (1 mL) at ca –10° (acetone-ice bath) was
added nitric acid (0.5 mL) dropwise over 15 minutes. The resultant
acetyl nitrate was added, dropwise, to a suspension of the N-
methoxy compound 8 (0.10 g, 0.42 mmol) in acetic anhydride (3
mL) over 10 minutes. The whole was allowed to warm to room
temperature and was then heated at 50° for 30 minutes. The solu-
tion was cooled, ice was added, and the phase was adjusted to pH 5
with 10% sodium hydroxide. The solid was collected by filtration
and washed with water to render 23 as a yellow solid (0.07 g,
6
4.04 (s, 3H, ArCH ), 7.87 (t, J = 7.7 Hz, 1H, H-8), 8.39 (dd, J =
3
7.1, 1.4 Hz, 1H, H-7), 8.66 (dd, J = 8.3, 1.2 Hz, 1H, H-9), 8.71 (s,
13
1H, H-3), 9.51 (s, 1H, H-10), 11.39 (s, 1H, CHO); C nmr
(dimethyl sulfoxide-d , 100°): δ 64.9 (OCH ), 98.9 (C), 121.4
6
3
(C), 126.2 (C-9a), 127.0 (C-8), 131.2 (C-6), 132.4 (C-7), 135.9
(C-9), 136.6 (C-3), 139.5 (C-10), 148.4 (C-4a), 148.9 (C-5a),
157.0 (C-1), 191.3 (CHO).
Anal. Calcd. for C H BrN O : C, 50.48; H, 2.72; N, 8.41.
14
9
2 3
1
Found: C, 50.36; H, 3.01; N, 8.14.
59%), mp 229–232° (ethanol); H nmr (dimethyl sulfoxide-d ): δ
6

Mar-Apr 2006
Novel Derivatives of the Benzo[b][1,6]naphthyridine System
413
2.71 (s, 3H, ArCH ), 4.09 (s, 3H, OCH ), 7.61 (t, J = 7.6 Hz, 1H,
2-Hydroxy-6-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyri-
dine-4-sulfonic Acid (26).
3
3
H-8), 7.83 (d, J = 6.9 Hz, 1H, H-7), 8.11 (d, J = 8.2 Hz, 1H, H-9),
13
9.33 (s, 1H, H-10), 9.40 (s, 1H, H-3); C nmr (dimethyl sulfoxide-
From the N-hydroxy compound 4a (1.84 g, 8.14 mmol) and
chlorosulfonic acid (5 mL), as for the sulfonic acid 25, except
that the reaction was only heated for 5 hours, and the orange sul-
fonic acid 26 was obtained as its hydrochloride (1.94 g, 70%), mp
>300°. This solid was used in this state in further reactions.
The free acid was liberated for nmr data and microanalysis.
The hydrochloride (0.20 g, 0.58 mmol) was stirred in 10%
sodium hydroxide (2 mL) for 10 minutes and the solution was fil-
tered. The filtrate was taken to pH 4 with concentrated
hydrochloric acid, cooled on ice, and the resultant sulfonic acid
26 was collected by filtration and was obtained as an orange solid
(0.14 g, 78% from the hydrochloride) mp >300°. A solution in
d ): δ 17.3 (ArCH ), 65.5 (CH Br), 119.3 (C), 125.9 (C-9a), 127.6
6
3
2
(C-9), 127.7 (C-8), 129.4 (C), 133.2 (C-7), 136.6 (C-6), 138.1 (C-
3), 139.1 (C-10), 142.2 (C-4a), 148.6 (C-5a), 157.7 (C-1).
Anal. Calcd. for C H N O : C, 58.95; H, 3.89; N, 14.73.
14 11
3 4
Found: C, 58.87; H, 3.79; N, 14.83.
2-Methoxy-6-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyri-
dine-4-sulfonyl Chloride (24) or 2-Methoxy-6-methyl-1-oxo-1,2-
dihydrobenzo[b][1,6]naphthyridine-4-sulfonic Acid (25).
The N-methoxy compound 8 (2.49 g, 10.38 mmol) and chloro-
sulfonic acid (5 mL) were heated at 70° for 16 hours. Ice (ca 100
mL) was cautiously added to the cooled solution and the resultant
suspension was stirred for 1 hour. The solid was collected by fil-
tration and washed with a little cold water to give a mixture of the
sulfonic acid 25 and the sulfonyl chloride 24, as their hydrochlo-
rides (3.06 g). Then:
(a) To this dried mixture was added thionyl chloride (35 mL)
and N,N-dimethylformamide (1 mL), and the suspension was
heated under reflux for 45 minutes, during which time dissolution
occurred. The volatiles were removed under reduced pressure
and residual thionyl chloride was azeotropically distilled with
benzene. The solid was partitioned between cold
dichloromethane and ice-cold 10% potassium carbonate, and the
organic phase was washed once more with cold base and then
with cold brine (× 2). The organic phase was dried over magne-
sium sulfate, filtered and the filtrate was evaporated under
reduced pressure to give the sulfonyl chloride 24 (2.84 g, 81%) as
a yellow solid which was used directly in further reactions. A
sample for data was purified by flash column chromatography
3+
1
ethanol gave a deep red coloration upon the addition of Fe ; H
nmr (dimethyl sulfoxide-d ): δ 2.74 (s, 3H, ArCH ), 7.81 (t, J =
6
3
7.6 Hz, 1H, H-8), 8.13 (d, J = 6.9 Hz, 1H, H-7), 8.40 (d, J = 8.2
13
Hz, 1H, H-9), 8.57 (s, 1H, H-3), 9.94 (s, 1H, H-10); C nmr
(dimethyl sulfoxide-d ): δ 16.1 (ArCH ), 114.7 (C), 120.4 (C),
6
3
125.6 (C-6), 128.6 (C-8), 128.8 (C-9a), 129.0 (C-9), 138.1 (C-7),
139.1 (C-5a), 142.1 (C-4a), 142.2 (C-3), 148.0 (C-10), 156.7
+
(C-1); esms: m/z 307.2 (M+H) .
Anal. Calcd. for C H N O S•0.25H O: C, 50.24; H, 3.41;
13 10
2
5
2
N, 9.01. Found: C, 50.35; H, 3.60; N, 8.93.
1-Chloro-6-methylbenzo[b][1,6]naphthyridine-4-sulfonyl
Chloride (27).
From the hydrochloride of the sulfonic acid 26 (1.94 g, 5.66
mmol), as for the sulfonyl chloride 24, and the chlorosulfonyl
chloride 27 was obtained as an orange solid (1.66 g, 90%), mp
1
228–232° (dec.), sufficiently pure for further reactions; H nmr
(deuteriochloroform): δ 3.00 (s, 3H, ArCH ), 7.68 (dd, J = 8.3, 7.0
3
Hz, 1H, H-8), 7.91 (d, J = 6.9 Hz, 1H, H-7), 8.02 (d, J = 8.4 Hz,
[ethyl acetate–hexane (3:7); R , 0.6] and recrystallized from
f
13
1H, H-9), 9.15 (s, 1H, H-3), 9.34 (s, 1H, H-10); C nmr (deuteri-
petroleum spirit (bp 80–110°). On slow heating the solid changed
ochloroform): δ 17.7 (ArCH ), 120.7 (C), 126.6 (C-9), 127.5 (C-
3
form at ca 205° and, while some melted >225°, the mp was
9a), 128.6 (C-8), 133.9 (C-7), 134.3 (C), 137.3 (C-10), 138.5 (C-
6), 142.7 (C-4a), 145.0 (C-3), 151.1 (C-5a), 159.8 (C-1).
1
>300°. On rapid heating, the solid melted slowly 225–240°; H
nmr (deuteriochloroform): δ 2.91 (s, 3H, ArCH ), 4.21 (s, 3H,
3
OCH ), 7.58 (d, J = 7.6 Hz, 1H, H-8), 7.79 (d, J = 6.9 Hz, 1H, H-
4-(6-Methyl-1-(4-morpholino)benzo[b][1,6]naphthyridine-4-sul-
fonyl)morpholine (28).
3
7), 7.87 (d, J = 8.3 Hz, 1H, H-9), 8.62 (s, 1H, H-3), 9.24 (s, 1H,
13
H-10); C nmr (deuteriochloroform): δ 17.5 (ArCH ), 65.5
3
To the sulfonyl chloride 27 (0.24 g, 0.73 mmol) dissolved in
dichloromethane (25 mL) on a salt-ice bath was added triethy-
lamine (0.37 g, 3.66 mmol) in dichloromethane (2 mL) in one por-
tion, followed by morpholine (0.14 g, 1.61 mmol) in
dichloromethane (5 mL) dropwise. After stirring for 0.5 hour, the
reaction was allowed to warm to room temperature and stirring
was continued for 16 hours under a positive pressure of nitrogen.
The solution was diluted with more dichloromethane and washed
with 10% potassium carbonate, followed by 3% hydrochloric acid
and then with water (× 3). The organic phase was dried over mag-
nesium sulfate, filtered and the filtrate was evaporated under
reduced pressure to give the sulfonamide 28 (0.26 g, 83%). Two
recrystallizations from petroleum spirit (bp 80–110°)
–dichloromethane, with decantation from an initially-formed oil,
(OCH ), 119.1 (C), 120.4 (C), 125.9 (C-9a), 126.5 (C-9), 127.9
3
(C-8), 133.0 (C-7), 138.2 (C-6), 138.9 (C-10), 139.8 (C-3), 142.9
(C-4a), 149.3 (C-5a), 158.0 (C-1).
or (b) A portion of this solid (0.32 g) was suspended and
stirred in 10% potassium carbonate (30 mL) for 8 h, then acidi-
fied to pH 4 with concentrated hydrochloric acid and evaporated
to dryness under reduced pressure. The solids were stirred in hot
ethanol, and the liquid was filtered. After repeating this extrac-
tion twice more, the ethanol was evaporated under reduced pres-
sure to leave the yellow sulfonic acid 25 (0.26 g, 69% from 8),
1
mp 300–302° (after darkening at 295°) (acetonitrile); H nmr
(dimethyl sulfoxide-d ): δ 2.75 (s, 3H, ArCH ), 4.06 (s, 3H,
6
3
OCH ), 7.77 (t, J = 7.7 Hz, 1H, H-8), 8.06 (d, J = 7.0 Hz, 1H, H-
3
1
7), 8.33 (d, J = 8.2 Hz, 1H, H-9), 8.71 (s, 1H, H-3), 9.79 (s, 1H,
gave a yellow solid, mp 197–205°; H nmr (dimethyl sulfoxide-
13
H-10); C nmr (dimethyl sulfoxide-d ): δ 16.2 (ArCH ), 65.5
d ): δ 2.76 (s, 3H, ArCH ), 3.23–3.26 [m, 4H, N(CH ) -4],
6
3
6
3
2 2
(OCH ), 116.5 (C), 121.1 (C), 125.6 (C), 128.7 (C-8), 128.9 (C-
3.52–3.55 [m, 4H, O(CH ) -4], 3.83 [br s, 8H, N(CH ) -1,
3
2 2
2 2
9), 129.6 (C), 137.8 (C-7), 139.6 (C-5a), 141.2 (C-3), 143.1 (C-
4a), 147.1 (C-10), 155.9 (C-1).
O(CH ) -1], 7.56 (t, J = 7.6 Hz, 1H, H-8), 7.81 (d, J = 6.8 Hz, 1H,
2 2
H-7), 8.12 (d, J = 8.2 Hz, 1H, H-9), 8.63 (s, 1H, H-3), 9.22 (s, 1H,
13
Anal. Calcd. for C H N O S: C, 52.50; H, 3.78; N, 8.75.
H-10); C nmr (dimethyl sulfoxide-d ): δ 18.1 (ArCH ), 46.3
14 12
2 5
6
3
Found: C, 52.60; H, 3.78; N, 9.06.
[N(CH ) -4], 50.9 [N(CH ) -1], 65.9 [O(CH ) -4], 66.2
2 2
2 2
2 2

414
L. W. Deady and M. L. Rogers
Vol. 43
[O(CH ) -1], 113.0 (C), 119.4 (C), 125.4 (C-9a), 126.4 (C-8),
Anal. Calcd. for C H N O S: C, 61.60; H, 4.68; N, 10.26.
21 19 3 4
2 2
127.8 (C-9), 132.9 (C-7), 136.0 (C-6), 137.4 (C-10), 147.1 (C-4a),
148.8 (C-5a), 149.1 (C-3), 163.8 (C-1); esms: m/z 429.6 (M+H) .
Found: C, 61.64; H, 4.70; N, 10.13.
+
2-Methoxy-6-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyri-
dine-4-sulfonamide (30).
Anal. Calcd. for C H N O S: C, 58.86; H, 5.65; N, 13.07.
21 24
4 4
Found: C, 58.64; H, 5.43; N, 13.04.
From the sulfonyl chloride 24 (1.55 g, 4.58 mmol) and a
stream of ammonia gas for 20 minutes, as for the sulfonamide 31,
except that, after reaction, the volatiles were evaporated under
reduced pressure, ice-water was added and the solid was col-
lected by filtration and washed with water to give 30 as a mustard
coloured solid (1.24 g, 85%), mp 231–237° (toluene). After being
dried at 150° at ca 0.01 mmHg for 24 hours, ca 10% toluene
N-[2-(Dimethylamino)ethyl]-1-[2-(dimethylamino)ethylamino]-
6-methylbenzo[b][1,6]naphthyridine-4-sulfonamide (29).
From the sulfonyl chloride 27 (0.26 g, 0.79 mmol) and N,N-
dimethylethylenediamine (0.15 g, 1.70 mmol), as for 28, except
that, after reaction, the solution was not washed with acid. The
crude orange-brown sulfonamide 29 (0.20 g) was dissolved in
tetrahydrofuran (40 mL) and hydrogen chloride gas was bubbled
through the solution for 10 minutes. Diethyl ether was added, and
the liquids were decanted from a sticky brown solid. This solid
was washed twice more (with decantation) with diethyl ether and
then recrystallized from aqueous ethanol–ether to give 29 as its
yellow trihydrochloride salt (hygroscopic) (0.14 g, 33%), mp
195–200°.
1
remained; H nmr (dimethyl sulfoxide-d ): δ 2.75 (s, 3H,
6
ArCH ), 4.07 (s, 3H, OCH ), 7.05 (s, 2H, SO NH ), 7.56 (t, J =
3
3
2
2
7.6 Hz, 1H, H-8), 7.79 (d, J = 6.8 Hz, 1H, H-7), 8.05 (d, J = 8.2
13
Hz, 1H, H-9), 8.58 (s, 1H, H-3), 9.27 (s, 1H, H-10); C nmr
(dimethyl sulfoxide-d ): δ 17.8 (ArCH ), 65.2 (OCH ), 119.3
6
3
3
(C), 120.0 (C), 125.7 (C-9a), 127.4 (C-8), 127.5 (C-9), 133.1 (C-
7), 136.3 (C-6), 136.8 (C-3), 139.1 (C-10), 145.0 (C-4a), 148.2
+
Anal. Calcd. for C H N O S•3HCl: C, 46.71; H, 6.16; N,
(C-5a), 157.7 (C-1); esms: m/z 319.9 (M+H) .
21 30
6 2
15.56. Found: C, 46.62; H, 6.40; N, 15.30.
Anal. Calcd. for C H N O S•0.1C H : C, 53.74; H, 4.23; N,
14 13 3 4 7 8
The free base was liberated as an orange-brown solid, mp
12.79. Found: C, 53.66; H, 4.17; N, 13.09.
1
66–70°; H nmr (deuteriochloroform): δ 1.58 [s, 6H, N(CH ) -
3 2
N-[2-(Dimethylamino)ethyl]-2-methoxy-6-methyl-1-oxo-1,2-
dihydrobenzo[b][1,6]naphthyridine-4-sulfonamide (32).
4], 2.22 (t, J = 5.6 Hz, 2H, CH CH NMe -4), 2.43 [s, 6H,
2
2
2
N(CH ) -1], 2.78–2.86 (m, 7H, ArCH , CH CH NMe -4,
3 2
3
2
2
2
From the sulfonyl chloride 24 (0.21 g, 0.62 mmol) and N,N-
dimethylethylenediamine (0.07 g, 0.79 mmol), as for the sulfon-
amide 31, except that, after reaction, the dichloromethane solu-
tion was not washed with acid, and the crude sulfonamide 32 was
obtained as an orange-brown solid (0.15 g, 62%). Two recrystal-
CH CH NMe -1), 3.74 (t, J = 5.6 Hz, 2H, CH CH NMe -1),
6.79 (br s, 1H, NH-4), 7.35 (t, J = 7.6 Hz, 1H, H-8), 7.57 (d, J =
2
2
2
2
2
2
6.7 Hz, 1H, H-7), 7.76 (d, J = 8.3 Hz, 1H, H-9), 8.66 (s, 1H, H-3),
13
8.78 (s, 1H, H-10) (NH-1 was not observed); C nmr (deuteri-
ochloroform): δ 17.6 (ArCH ), 38.4 (CH CH NMe -1), 40.5
3
2
2
2
1
lizations from toluene gave a fawn solid, mp 168–175°; H nmr
(CH CH NMe -4), 43.8 [N(CH ) -4], 44.6 [N(CH ) -1], 56.5
2
2
2
3 2
3 2
(deuteriochloroform): δ 1.80 [s, 6H, N(CH ) ], 2.40 (t, J = 5.5
(CH CH NMe -4), 57.1 (CH CH NMe -1), 111.7 (C), 116.6
3 2
2
2
2
2
2
2
Hz, 2H, CH CH NMe ), 2.89 (s, 3H, ArCH ), 3.01 (q, J = 4.3
(C), 125.3 (C-9a), 126.0 (C-8), 126.6 (C-9), 131.8 (C-7), 132.7
(C-10), 136.4 (C-6), 144.9 (C-4a), 148.6 (C-5a), 149.2 (C-3),
158.4 (C-1).
2
2
2
3
Hz, 2H, CH CH NMe ), 4.18 (s, 3H, OCH ), 6.76 (br s, 1H,
2
2
2
3
NH), 7.54 (t, J = 7.6 Hz, 1H, H-8), 7.76 (d, J = 6.9 Hz, 1H, H-7),
7.87 (d, J = 8.2 Hz, 1H, H-9), 8.44 (s, 1H, H-3), 9.27 (s, 1H, H-
N-Benzyl-2-methoxy-6-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]-
naphthyridine-4-sulfonamide (31).
13
10); C nmr (deuteriochloroform): δ 17.7 (ArCH ), 40.3
3
(CH CH NMe ), 43.9 [N(CH ) ], 56.4 (CH CH NMe ), 65.0
2
2
2
3 2
2
2
2
To the sulfonyl chloride 24 (0.13 g, 0.38 mmol) dissolved in
dichloromethane (20 mL) on a salt-ice bath was added triethy-
lamine (0.12 g, 1.19 mmol) in dichloromethane (2 mL), followed
by benzylamine (0.05 g, 0.47 mmol) in dichloromethane (5 mL)
dropwise. After being stirred for 0.5 hour, the reaction was
allowed to warm to room temperature and stirring was continued
for 16 hours under a positive pressure of nitrogen. The solution
was diluted with more dichloromethane and washed with 10%
potassium carbonate, followed by 3% hydrochloric acid and then
with water (× 3). The organic phase was dried over magnesium
sulfate, filtered and the filtrate was evaporated under reduced
pressure to give the sulfonamide 31 as a pale yellow solid (0.12 g,
76%), with mp 173–176° after two recrystallizations from petro-
(OCH ), 115.0 (C), 119.7 (C), 125.9 (C-9a), 126.8 (C-9), 127.4
(C-8), 132.9 (C-7), 137.1 (C-6), 137.9 (C-3), 139.1 (C-10), 144.4
(C-4a), 148.9 (C-5a), 158.1 (C-1).
3
Anal. Calcd. for C H N O S: C, 55.37; H, 5.68; N, 14.35.
18 22
4 4
Found: C, 55.61; H, 5.51; N, 14.47.
4-(2-Methoxy-6-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naph-
thyridine-4-sulfonyl)morpholine (33).
From the sulfonyl chloride 24 (2.45 g, 7.23 mmol) and morpho-
line (0.76 g, 8.72 mmol), as for the sulfonamide 31, and 33 was
obtained as an orange foam (2.41 g, 86%). A sample was recrystal-
lized from toluene to give a pale yellow solid with mp 232–242°,
which retained ca 10% toluene after drying at 150° and ca 0.01
1
1
mmHg for 24 hours; H nmr (deuteriochloroform): δ 2.82 (s, 3H,
leum spirit (bp 80–110°)–dichloromethane; H nmr (deuteri-
ArCH ), 3.43–3.46 [m, 4H, N(CH ) ], 3.67–3.70 [m, 4H, O(CH ) ],
ochloroform): δ 2.69 (s, 3H, ArCH ), 4.16 (s, 5H, OCH ,
3
2 2
2 2
3
3
4.16 (s, 3H, OCH ), 7.52 (t, J = 7.6 Hz, 1H, H-8), 7.73 (d, J = 6.8 Hz,
NHCH ), 6.49 (br s, 1H, NH), 6.99–7.05 (m, 5H, Ph), 7.55 (t, J =
3
2
1H, H-7), 7.84 (d, J = 8.2 Hz, 1H, H-9), 8.50 (s, 1H, H-3), 9.24 (s,
7.6 Hz, 1H, H-8), 7.74 (d, J = 6.8 Hz, 1H, H-7), 7.88 (d, J = 8.2
Hz, 1H, H-9), 8.37 (s, 1H, H-3), 9.23 (s, 1H, H-10); C nmr
13
13
1H, H-10); C nmr (deuteriochloroform): δ 18.4 (ArCH ), 46.1
3
[N(CH ) ], 65.0 (OCH ), 66.3 [O(CH ) ], 115.5 (C), 119.8 (C),
(deuteriochloroform): δ 18.0 (ArCH ), 47.8 (NHCH ), 65.0
2 2
3
2 2
3
2
125.8 (C-9a), 126.8 (C-9), 127.3 (C-8), 133.0 (C-7), 137.1 (C-6),
139.0 (C-10), 139.8 (C-3), 145.0 (C-4a), 149.2 (C-5a), 158.1 (C-1).
Anal. Calcd. for C H N O S•0.1C H : C, 56.34; H, 5.01; N,
(OCH ), 115.7 (C), 119.8 (C), 125.9 (C-9a), 127.0 (C-9), 127.4
3
(CH), 127.5 (CH), 127.8 (2 × CH, Ph), 127.9 (2 × CH, Ph), 133.2
(C-7), 135.2 (C-1′), 136.1 (C-6), 137.7 (C-3), 139.3 (C-10), 144.4
(C-4a), 148.6 (C-5a), 157.9 (C-1).
18 19
3
5
7 8
10.54. Found: C, 56.27; H, 4.97; N, 10.49.

Mar-Apr 2006
Novel Derivatives of the Benzo[b][1,6]naphthyridine System
415
N-(2-Methoxy-6-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naph-
thyridine-4-sulfonyl)piperidine (34).
under gentle reflux for 16 hours. The reaction mixture was
cooled, filtered and the solid was washed with acetone. This
solid was suspended in 3% hydrochloric acid, refiltered and
washed with water (0.19 g). Recrystallization from toluene gave
an analytically pure sample; the toluene filtrate contained more
of the target but in a less pure state. The pure sulfonyl urea 37
was thus obtained as a pale yellow solid (0.08 g, 28%), mp
From the sulfonyl chloride 24 (0.44 g, 1.30 mmol) and piperi-
dine (0.13 g, 1.53 mmol), as for the sulfonamide 31, and 34 was
obtained as an orange foam (0.43 g, 85%). A cream solid with mp
220–223° was obtained after two recrystallizations from petro-
1
leum spirit (bp 80–110°)–toluene; H nmr (deuteriochloroform):
1
197–202°; H nmr (dimethyl sulfoxide-d ): δ 2.82 (s, 3H,
6
δ 1.41–1.48 (m, 2H, piperidinyl-4-CH ), 1.56–1.64 (m, 4H,
2
ArCH ), 4.06 (s, 5H, OCH , CH ), 6.79–6.89 (m, 4H, H-2′, H-
3
3
2
piperidinyl-3,5-CH ), 2.88 (s, 3H, ArCH ), 3.41–3.45 (m, 4H,
2
3
6′, H-3′, H-5′), 6.98–7.03 (m, 1H, H-4′), 7.09 (t, J = 5.9 Hz, 1H,
piperidinyl-2,6-CH ), 4.16 (s, 3H, OCH ), 7.54 (dd, J = 7.9, 7.3
2
3
NHCH —exchanged with added deuterium oxide), 7.61 (t, J =
2
Hz, 1H, H-8), 7.75 (d, J = 6.9 Hz, 1H, H-7), 7.88 (d, J = 8.2 Hz,
7.6 Hz, 1H, H-8), 7.82 (d, J = 6.8 Hz, 1H, H-7), 8.13 (d, J = 8.2
13
1H, H-9), 8.50 (s, 1H, H-3), 9.28 (s, 1H, H-10); C nmr (deuteri-
Hz, 1H, H-9), 8.71 (s, 1H, H-3), 9.35 (s, 1H, H-10), 10.04 (s, 1H,
ochloroform): δ 18.3 (ArCH ), 23.3 (piperidinyl-4-CH ), 25.4
3
2
13
SO NH—exchanged with added deuterium oxide); C nmr
2
(piperidinyl-3,5-CH ), 46.9 (piperidinyl-2,6-CH ), 64.9 (OCH ),
2
2
3
(dimethyl sulfoxide-d ): δ 18.2 (ArCH ), 42.4 (CH ), 65.4
6
3
2
116.5 (C), 119.8 (C), 125.8 (C-9a), 126.7 (C-9), 127.2 (C-8),
132.8 (C-7), 137.4 (C-6), 138.9 (C-10), 139.2 (C-3), 145.2 (C-
4a), 149.3 (C-5a), 158.2 (C-1).
(OCH ), 115.3 (C), 119.6 (C), 125.8 (C-9a), 126.4 (C-2′, C-6′),
3
126.7 (C-4′), 127.5 (C-9, C-8), 128.0 (C-3′, C-5′), 133.1 (C-7),
137.0 (C-6), 139.0 (C-1′), 139.2 (C-10), 141.7 (C-3), 144.6 (C-
4a), 148.6 (C-5a), 151.4 (urea CO), 157.9 (C-1).
Anal. Calcd. for C H N O S: C, 58.90; H, 5.46; N, 10.84.
19 21
3 4
Found: C, 59.19; H, 5.62; N, 10.92.
Anal. Calcd. for C H N O S: C, 58.40; H, 4.46; N, 12.38.
22 20
4 5
2-Hydroxy-6-methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyri-
dine-4-sulfonamide (36).
Found: C, 58.35; H, 4.46; N, 12.29.
4-Bromo-6-methylbenzo[b][1,6]naphthyridin-1(2H)-one (38).
The sulfonamide 30 (0.20 g, 0.63 mmol), 40% hydrobromic acid
(6 mL) and acetic acid (2 mL) were heated under reflux at 130° for
16 hours. The resultant solution was cooled, ice (100 g) was added,
and the phase was adjusted to pH 5 with 10% sodium hydroxide.
The solid was collected by filtration to give a mixture of the target
sulfonamide and the starting material (1.6:1). The brown solid
(0.13 g) was allowed to dry overnight, boiled in ethanol (80 mL)
(sonication was initially required to break up the solid), filtered
while hot and the hot filtrate was added to silica gel (12 g) with
swirling. The ethanol was removed under reduced pressure with
constant rotary evaporation and dried at 40° overnight; this ren-
dered the compounds homogeneously adsorbed to the silica gel.
The silica was washed with ethyl acetate–hexane (1:1) until no
The bromo-N-methoxy compound 15 (0.20 g, 0.63 mmol) and an
equal weight of potassium hydroxide in N,N-dimethylformamide
(10 mL) were heated at 100° for 0.5 hour with constant stirring. The
reaction mixture was filtered, the volatiles were removed from the
filtrate under reduced pressure, and ice-water was added. The whole
was acidified with 3% hydrochloric acid, and the yellow solid was
collected by filtration to give 38 (0.13 g, 72%), mp >300° (after
1
gradually darkening >270°) (n-propanol × 2); H nmr (dimethyl
sulfoxide-d ): δ 2.76 (s, 3H, ArCH ), 7.53 (t, J = 7.6 Hz, 1H, H-8),
6
3
7.77 (d, J = 6.9 Hz, 1H, H-7), 7.83 (d, J = 4.5 Hz, 1H, H-3), 8.05 (d,
13
J = 8.2 Hz, 1H, H-9), 9.17 (s, 1H, H-10), 11.57 (br s, 1H, NH);
C
nmr (dimethyl sulfoxide-d ): δ 17.5 (ArCH ), 100.4 (C), 120.7 (C),
6
3
126.3 (C-9a), 126.7 (C-8), 127.4 (C-9), 132.5 (C-7), 134.0 (C-3),
136.3 (C-6), 138.5 (C-10), 148.2 (C-4a), 149.0 (C-5a), 162.1 (C-1);
starting material eluted (R , 0.5). The silica gel was stirred in N,N-
f
dimethylformamide (25 mL) for 1 hour, and decanted and filtered.
After repeating this extraction process twice more, the N,N-
dimethylformamide was evaporated at reduced pressure, 3%
hydrochloric acid was added and the title compound 36 was col-
lected by filtration and obtained as brown needles after recrystal-
lization from ethanol (0.06 g, 31%), mp 266–268°. Evaporation of
the ethyl acetate–hexane eluate recovered the starting material 30
+
esms: m/z 291.3, 289.3; both (M+H) .
Anal. Calcd. for C H BrN O: C, 54.00; H, 3.14; N, 9.69.
13
9
2
Found: C, 54.22; H, 3.39; N, 9.79.
4-(6-Methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyridine-4-
sulfonyl)morpholine (39).
From the sulfonamide 33 (0.46 g, 1.18 mmol), as for 38, and 39
(0.04 g, 20%). A solution of 36 in ethanol gave a deep red col-
was obtained as an orange-brown solid (0.29 g, 68%), mp
3+ 1
oration upon the addition of Fe ; H nmr (dimethyl sulfoxide-d ):
6
1
271–275° (after gradually forming needles ca 200°) (ethanol); H
δ 2.78 (s, 3H, ArCH ), 7.03 (s, 2H, SO NH ), 7.59 (t, J = 7.3 Hz,
3
2
2
nmr (dimethyl sulfoxide-d ): δ 2.74 (s, 3H, ArCH ), 3.26–3.29 [m,
6
3
1H, H-8), 7.82 (d, J = 5.9 Hz, 1H, H-7), 8.11 (d, J = 8.1 Hz, 1H, H-
4H, N(CH ) ], 3.53–3.56 [m, 4H, O(CH ) ], 7.56 (t, J = 7.6 Hz,
2 2
2 2
13
9), 8.36 (s, 1H, H-3), 9.36 (s, 1H, H-10), 12.11 (s, 1H, OH);
C
1H, H-8), 7.79 (d, J = 6.9 Hz, 1H, H-7), 8.05–8.09 (m, 2H, H-3, H-
nmr (dimethyl sulfoxide-d ): δ 17.9 (ArCH ), 118.2 (C), 119.6 (C),
6
3
13
9), 9.24 (s, 1H, H-10), 11.97 (d, J = 6.4 Hz, 1H, NH); C nmr
125.8 (C-9a), 127.3 (C-8), 127.6 (C-9), 133.0 (C-7), 136.4 (C-6),
137.5 (C-3), 139.0 (C-10), 144.9 (C-4a), 148.4 (C-5a), 158.6 (C-1);
(dimethyl sulfoxide-d ): δ 18.1 (ArCH ), 46.1 [N(CH ) ], 65.9
6
3
2 2
[O(CH ) ], 114.2 (C), 119.8 (C), 126.1 (C-9a), 127.0 (C-8), 127.7
2 2
+
esms: m/z 306.4 (M+H) .
(C-9), 132.9 (C-7), 136.4 (C-6), 138.6 (C-10), 141.0 (C-3), 147.2
Anal. Calcd. for C H N O S: C, 51.14; H, 3.63; N, 13.76.
13 11
3 4
+
(C-4a), 148.6 (C-5a), 162.6 (C-1); esms: m/z 360.2 (M+H) .
Found: C, 50.79; H, 3.81; N, 13.50.
Anal. Calcd. for C H N O S: C, 56.81; H, 4.77; N, 11.69.
17 17
3 4
N-[(Benzylamino)carbonyl]-2-methoxy-6-methyl-1-oxo-1,2-
dihydrobenzo[b][1,6]naphthyridine-4-sulfonamide (37).
Found: C, 56.93; H, 4.87; N, 11.63.
4-(1-Chloro-6-methylbenzo[b][1,6]naphthyridine-4-
sulfonyl)morpholine (35).
To a suspension of the sulfonamide 30 (0.20 g, 0.63 mmol)
and potassium carbonate (0.86 g, 6.22 mmol) in acetone (20 mL)
was added, in one portion, benzyl isocyanate (0.25 g, 1.88
mmol) dissolved in acetone (20 mL), and the whole was heated
(a) Preferred method: The 1-oxo sulfonamide 39 (0.29 g, 0.81
mmol) and phosphoryl chloride (5 mL) were heated under gentle

416
L. W. Deady and M. L. Rogers
Vol. 43
reflux for 8 hours. The excess phosphoryl chloride was removed
under vacuum, ice-water was added and the product was extracted
with dichloromethane. The organic phase was washed with 10%
sodium carbonate, followed by brine (× 3), and was evaporated to
dryness under reduced pressure to give 35 as a brown foam (0.28 g,
92%), which was used in this state in further reaction. A chro-
matographed sample [method (b), below] was obtained as yellow
4H, N(CH ) ], 3.52–3.55 [m, 4H, O(CH ) ], 4.88 (d, J = 5.6 Hz,
2 2 2 2
2H, NHCH ), 7.21–7.26 (m, 1H, H-4′), 7.29–7.34 (m, 2H, H-3′,
2
H-5′), 7.40–7.43 (m, 2H, H-2′, H-6′), 7.56 (t, J = 7.6 Hz, 1H, H-8),
7.80 (d, J = 6.8 Hz, 1H, H-7), 7.90 (d, J = 8.2 Hz, 1H, H-9), 8.56 (s,
13
1H, H-3), 9.42 (t, J = 5.7 Hz, 1H, NH), 9.56 (s, 1H, H-10); C nmr
(dimethyl sulfoxide-d ): δ 18.1 (ArCH ), 44.6 (NHCH ), 46.3
6
3
2
[N(CH ) ], 65.9 [O(CH ) ], 112.6 (C), 116.0 (C), 125.7 (C-9a),
2 2
2 2
1
needles and had mp 225–228°; H nmr (deuteriochloroform): δ
126.6 (C-8), 127.09 (C-4′), 127.13 (C-9), 127.7 (C-2′, C-6′), 128.5
(C-3′, C-5′), 132.5 (C-7), 134.5 (C-10), 136.4 (C-6), 138.9 (C-1′),
146.4 (C-4a), 148.8 (C-5a), 152.2 (C-3), 159.7 (C-1).
2.92 (s, 3H, ArCH ), 3.46–3.49 [m, 4H, N(CH ) ], 3.68–3.71 [m,
3
2 2
4H, O(CH ) ], 7.63 (dd, J = 8.3, 7.0 Hz, 1H, H-8), 7.85 (d, J = 6.8
2 2
Hz, 1H, H-7), 8.00 (d, J = 8.4 Hz, 1H, H-9), 9.08 (s, 1H, H-3), 9.32
Anal. Calcd. for C H N O S: C, 64.27; H, 5.39; N, 12.49.
Found: C, 64.40; H, 5.47; N, 12.46.
24 24
4 3
13
(s, 1H, H-10); C nmr (deuteriochloroform): δ 18.5 (ArCH ), 46.1
3
[N(CH ) ], 66.3 [O(CH ) ], 120.5 (C), 126.9 (C-9), 127.2 (C-9a),
2 2
2 2
128.0 (C-8), 129.1 (C), 133.7 (C-7), 137.3 (C-10), 137.4 (C-6),
REFERENCES AND NOTES
144.7 (C-4a), 147.0 (C-3), 150.9 (C-5a), 157.7 (C-1). Hrms Calcd.
+
for C H ClN O S [(M+H) ]: 378.0680. Found: 378.0672.
17 17
3 3
[1] L. W. Deady and T. Rodemann, J. Heterocyclic Chem., 38,
1185 (2001).
[2] L. W. Deady, T. Rodemann, L. Zhuang, B. C. Baguley and W.
A. Denny, J. Med. Chem., 46, 1049 (2003).
[3] L. W. Deady, M. L. Rogers, L. Zhuang, B. C. Baguley and W.
A. Denny, Bioorg. Med. Chem., 13, 1341 (2005).
[4] J. N. Chatterjea, S. K. Mukherjee and C. Bhakta, J. Ind. Chem.
Soc., 59, 707 (1982).
[5] M. M. Robison and B. L. Robison, J. Am. Chem. Soc., 80,
3443 (1958).
[6] D. E. Horning, G. Lacasse and J. M. Muchowski, Can. J.
Chem., 49, 2785 (1971).
[7] R. A. Henry, C. A. Heller and D. W. Moore, J. Org. Chem.,
40, 1760 (1975).
[8] L. W. Deady, S. M. Devine and M. L. Rogers, Org. Prep. and
Proced. Int., 35, 627 (2003).
[9] J. Y. Q. Lai, Y. Ferguson and M. Jones, Synthetic Commun.,
33, 3427 (2003).
(b) This compound was also obtained, in lower yield and by a
more complex procedure, from reaction of the chlorosulfonyl
chloride 27 with an equimolar amount of morpholine, as follows:
To a solution of the sulfonyl chloride 27 (181.4 mg, 0.55
mmol) in dichloromethane (35 mL) at –18° (acetone-ice bath)
under a positive pressure of nitrogen was added a solution of tri-
ethylamine (56.1 mg, 0.55 mmol) in dichloromethane (1 mL) in
one portion, followed by a 36.7 mM solution of morpholine in
dichloromethane (15 mL, 0.55 mmol morpholine) dropwise over
10 minutes. The solution was stirred for 16 hours in the acetone-
ice bath and was then washed with cold 10% potassium carbon-
ate, followed by cold 3% hydrochloric acid, and cold water (× 3).
The organic layer was dried over magnesium sulfate, filtered, and
the filtrate was evaporated under reduced pressure to give a mix-
ture of products (210 mg). Plc separation [ethyl acetate–hexane
(1:1)] allowed isolation of the target chlorosulfonamide 35 (R ,
f
0.4–0.6) and the bis morpholino sulfonamide 28 (R , 0.1–0.2).
f
[10] A. Scozzafava, T. Owa, A. Mastrolorenzo and C. T. Supuran,
Curr. Med. Chem., 10, 925 (2003).
[11] J. G. Montana and J. H. Dyke, PCT Int. Appl. WO9744322;
Chem. Abstr., 128, 48150 (1997).
4-(1-Benzylamino-6-methylbenzo[b][1,6]naphthyridine-4-sul-
fonyl)morpholine (40).
To the chloro compound 35 (0.28 g, 0.74 mmol) dissolved in
dichloromethane (30 mL) under a positive pressure of nitrogen was
added triethylamine (0.23 g, 2.27 mmol) in dichloromethane (5
mL), followed by benzylamine (1.19 g, 11.10 mmol) in
dichloromethane (10 mL) in portions, and the solution was stirred
at room temperature for 16 hours (or until the reaction was com-
[12] M. Kawase, T. Kitamura, M. Shimada and Y. Kikugawa,
Synthetic Commun., 20, 887 (1990).
[13] H. M. Faidallah, H. A. Albar, M. S. I. Makki and E. M.
Sharshira, Phosphorus, Sulfur and Silicon, 177, 685 (2002).
[14] S. L. Graham and T. H. Scholz, Tetrahedron Lett., 31, 6269
(1990).
[15] The cytotoxicity GI values are the concentrations corre-
50
plete by tlc—R 35, 0.6; R 40, 0.5). The volatiles were evaporated
f
f
sponding to 50% overall growth inhibition.
[16] Mean graph midpoint for growth inhibition of all human can-
cer cell lines successfully tested.
[17] This signal was concentration dependent and frequently
occurred as a broad singlet.
[18] This signal was concentration dependent and appeared
between δ 2.5 and 3.0 ppm.
[19] The compound readily rearranged to 12 during attempted
recrystallization.
under reduced pressure and some of the excess amine was removed
by azeotropic distillation with toluene (× 4) and then with diethyl
ether (× 4). The residue was triturated with diethyl ether and the
sulfonamide 40 was collected by filtration and washed with diethyl
ether, followed by 10% sodium carbonate and then exhaustively
with water, and was obtained as a bright yellow solid (0.19 g,
1
57%), mp 257–261° (after changing form >250°) (acetonitrile); H
nmr (dimethyl sulfoxide-d ): δ 2.77 (s, 3H, ArCH ), 3.19–3.22 [m,
6
3