Nitrosation of phenolic substrates under mildly basic conditions: Selective preparation of p-quinone monooximes and their antiviral activities

Article abstract of DOI:10.1021/jo951873s

Nitrosation of 3-methoxyphenol and 1-naphthol were examined under both acidic (NaNO₂-EtCO₂H-H₂O) and basic (i-AmNO₂-K₂CO₃-DMF) conditions. Acidic nitrosations afforded ortho-directed products, whereas para-directed nitrosations were observed under basic conditions to yield p-quinone monooximes. The basic para-directed nitrosation was further examined using 15 phenols, two naphthols, and four phenolic heterocyclics. A one-pot operation of the basic nitrosation followed by methylation with dimethyl sulfate gave the corresponding methyl ethers in high yield. Two p-quinone monooximes derived from 3-methoxyphenol and 8-hydroxyquinoline showed a moderate activity against HSV-1, and the latter oxime was also effective against HSV-2. On the other hand, p-quinone monooximes derived from methyl salicylate, 1-naphthol, 7-hydroxy-2-methylbenzo[b]furan, and 8-hydroxycoumarin showed the comparable activity to that of DDI against HIV-1.

Full text of DOI:10.1021/jo951873s

2774
J . Org. Chem. 1996, 61, 2774-2779
Nitr osa tion of P h en olic Su bstr a tes u n d er Mild ly Ba sic Con d ition s:
Selective P r ep a r a tion of p-Qu in on e Mon ooxim es a n d Th eir
An tivir a l Activities
Tsutomu Ishikawa,* Toshiko Watanabe, Hisashi Tanigawa, Tatsuru Saito, Ken-Ichiro Kotake,
Yoshiaki Ohashi, and Hisashi Ishii
Faculty of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi, Inage, Chiba 263, J apan
Received October 18, 1995X
Nitrosation of 3-methoxyphenol and 1-naphthol were examined under both acidic (NaNO2-
EtCO2H-H2O) and basic (i-AmNO2-K2CO3-DMF) conditions. Acidic nitrosations afforded ortho-
directed products, whereas para-directed nitrosations were observed under basic conditions to yield
p-quinone monooximes. The basic para-directed nitrosation was further examined using 15 phenols,
two naphthols, and four phenolic heterocyclics. A one-pot operation of the basic nitrosation followed
by methylation with dimethyl sulfate gave the corresponding methyl ethers in high yield. Two
p-quinone monooximes derived from 3-methoxyphenol and 8-hydroxyquinoline showed a moderate
activity against HSV-1, and the latter oxime was also effective against HSV-2. On the other hand,
p-quinone monooximes derived from methyl salicylate, 1-naphthol, 7-hydroxy-2-methylbenzo[b]-
furan, and 8-hydroxycoumarin showed the comparable activity to that of DDI against HIV-1.
Sch em e 1
In tr od u ction
Although aromatic nitrosation1 is restricted to only
highly reactive substrates such as phenols and anilines,
it is often used to directly introduce a nitrogen function
into aromatics. In the usual synthetic procedure, nitrous
acid is generated in situ by the neutralization of nitrite
salts with strong (aqueous) mineral acids which also
promotes the production of the active nitrosating agents.
Nitrosation of phenols basically occurs at the para
position to yield p-quinone monooximes,2 unless this is
blocked. However, ortho-nitrosation occurs in some
phenols; 1-naphthol gives a mixture of 2-(ortho-) and
4-(para-) nitrosated products in a ratio of 3:2 when
reacted with aqueous sodium nitrite (NaNO2) in acetic
acid.3 We have found that reacting 3-aryl-1-naphthol 1
with isoamyl nitrite (i-AmNO2) in dimethylformamide
(DMF) in the presence of potassium carbonate (K2CO3)
under nonaqueous conditions (basic nitrosation) exclu-
sively affords a 1,4-naphthoquinone monooxime which
following methylation yields the (Z)-ether 2,4 whereas
nitrosation did not proceed under the usual aqueous
acidic conditions (Scheme 1). Here, we present the scope
and limitations of the basic nitrosation of phenolic
substrates.
Resu lts a n d Discu ssion
Ba sic Nitr osa tion . Maleski6 has described the ortho-
directed nitrosation of 3-methoxyphenol (3) in propionic
acid using a limited amount of water to dissolve NaNO2
to give 5-methoxy-2-nitrosophenol2 (4) in 65% yield7 as
the only product. Reexamination of his method (method
A) resulted in the major formation (63%) of 4 together
with a small amount of an isomeric p-quinone monooxime
5. The ratio of 4 to 5 was 83%. The main product was
5 (39%; 72% of the products) when 3 was subjected to
basic nitrosation (method B).
We compared the nitrosation of 1-naphthol (6) under
both conditions. The major product of method A (63%;
74% of the products) was 2-nitroso-1-naphthol (7),8
whereas an isomeric 1,4-naphthoquinone 1-monooxime
(8) was the main product (59%; 69% of the products) of
method B.
Synthetic aromatic nitroso compounds have antiviral
activity, including that against the human immunodefi-
ciency virus (HIV).5 We therefore examined the antiviral
activities of some nitrosated products obtained under
basic conditions. Their antiviral activities against herpes
simplex virus types 1 and 2 (HSV-1 and HSV-2, respec-
tively) and HIV type 1 (HIV-1) are discussed.
X Abstract published in Advance ACS Abstracts, March 15, 1996.
(1) Coombes, R. G. In Comprehensive Organic Chemistry; Barton,
D., Ollis W. D., Eds.; Pergamon Press: Oxford, 1979; Vol. 2, pp 305-
381.
These results summarized in Table 1 suggested that
ortho- and para-directed nitrosation occurred in methods
A and B, respectively.
To rationalize the regioselectivities of the nitrosation
described above, MO calculations on protonated forms
(2) It is known that p-nitrosated phenols exist largely as the oxime
tautomer, but that o-nitroso derivatives exist as the nitroso tautomer,
in which intramolecular hydrogen bonding is of importance.1
(3) Benson, W. R.; Gajan, R. J . J . Org. Chem. 1966, 31, 2498.
(4) Ishikawa, T.; Saito, S.; Ishii, H. Tetrahedron 1995, 51, 8447.
(5) Rice, W. G.; Schaeffer, C. A.; Harten, B.; Villinger, F.; South, T.
L.; Summers, M. F.; Henderson, L. E.; Bess, J . W., J r.; Arthur, L. O.;
McDougal, J . S.; Orloff, S. L.; Mendeleyev, J .; Kun, E. Nature 1993,
361, 473.
(6) Maleski, R. J . Synth. Commun. 1993, 23, 343.
(7) Demonchaux et al. has described an alternative preparation of
4 in nearly the same yield under acidic conditions (NaNO2-H2SO4 in
H2O). Demonchaux, P.; Lenoir, P.; Augert, G.; Dupassieux, P. Bioorg.
Med. Chem. Lett. 1994, 4, 2383.
0022-3263/96/1961-2774$12.00/0 © 1996 American Chemical Society

Preparation of p-Quinoline Monooximes
J . Org. Chem., Vol. 61, No. 8, 1996 2775
Ta ble 1. Nitr osa tion of 3-Meth oxyp h en ol (3) a n d
1-Na p h th ol (6)
F igu r e 1. Selected electron densities in HOMOs of a proto-
nated form A, a neutral form B, and a deprotonated form C of
3-methoxyphenol (3) and 1-naphthol (6).
A on the hydroxy (OH) group, neutral forms B, and
deprotonated forms C were performed by the AM-1
method.9 We investigated HOMOs because the phenolic
substrates should act as nucleophiles in these nitrosation
reactions (Figure 1). In neutral forms B and deproto-
nated forms C of substrates 3 and 6, the highest electron
density was on C4 (para). In the protonated forms the
highest electron density of 3A was on C6 (ortho), whereas
the electron density on C2 (ortho) of 6A was quite low.
An orbital-controlled process should contribute to elec-
trophilic aromatic substitution with a noncationic spe-
cies.10 Thus, though additional factors must be taken
into consideration in the nitrosation of phenolic com-
pounds under acidic conditions, para-selectivity under the
weakly basic conditions in method B is supported by the
MO calculations.
Basic nitrosation using various phenolic substrates was
further examined to establish the scope and limitations
of the reaction (Table 2). Phenol itself (Table 2, run 1),
para-unsubstituted phenols activated with electron-
donating groups (EDGs) (Table 2, runs 2-4), and a
halogenated phenol (Table 2, run 5) efficiently yielded
the corresponding p-quinone monooximes. Phenols de-
activated with electron-withdrawing groups (EWGs) such
as salicylaldehyde (Table 2, run 6) and methyl salicylate
(Table 2, run 7) also could be nitrosated under slightly
vigorous conditions, but there was no nitrosation when
a carboxyl group was substituted as an EWG (Table 2,
run 8). Introducing a methoxy group to the para position
of the carbonyl group of salicylaldehyde lowered the yield
(Table 2, run 9), whereas more satisfactory results were
obtained by introducing a methyl group into the same
position of methyl salicylate (Table 2, run 10). Nitrosa-
tion was either ineffective or absent when a carbonyl
group was located at the meta position of the OH group
(Table 2, runs 11-13). Blocking the para position of the
OH group by a methyl group caused nitrosation to fail
(Table 2, run 15). The more reactive methoxy group led
to nitrosation/oxidation11 in which a nitro group was
introduced into the ortho position of the OH group, but
the yield was low (Table 2, run 14).
The basic nitrosation was further applied to naphthols
and some phenolic heterocyclics. Nitrosation proceeded
smoothly on 2-12 (Table 2, run 16) and 3-aryl-1-naph-
thols13 (Table 2, run 17) to give a single para-nitrosated
product from each. The products were isolated after
methylation in a one-pot reaction because of their relative
instability during isolation. A benzofuran derivative was
nitrosated to afford the desired product in moderate
yield14 (Table 2, run 18). On more electron-deficient
heterocyclics, the smooth introduction of a nitrogen
function occurred only when the para position of cou-
marin derivatives was unblocked (Table 2, runs 19 and
20). This basic nitrosation was also applicable to a
quinoline derivative (Table 2, run 21).
A variety of phenolic substrates were nitrosated under
mildly basic conditions to give quinone monooximes in
moderate to high yields, when the para positions were
(8) The presence of a nitroso tautomer on the 2-nitrosated 1-naph-
thol 7 in solution was controversial. 1H NMR studies showed that the
ratio of tautomeric mixtures was dependent on the polarity of the
solvent, namely an oxime/naphthol ratio of 2:1 in CDCl3 and a 100%
oxime population in DMSO-d6, respectively. (Geraldes, C. F. G. C.;
Silva, M. I. F. Opt. Pura Apl. 1988, 21, 71; Chem. Abstr. 1990, 112,
7140k.) An examination using 17O NMR has supported the above
findings, in which the absence of a nitroso tautomer was observed in
a mixed solution of acetonitrile and acetone (1:3). (Dahn, H.; Pechy,
P.; Flogel, R. Helv. Chim. Acta 1994, 77, 306.) We independently
reconfirmed that 7 exists as tautomeric mixtures in CDCl3 solution
from the 1H NMR spectra (see the Experimental Section).
(9) MO calculations were performed by the AM-1 method with
CAChe ver. 3.6.
(11) In some reactive aromatic compounds, nitrous acid-catalyzed
nitration has been reported.1
(12) Ishii, H.; Ishikawa, T.; Murota, M.; Aoki, Y.; Harayama, T. J .
Chem. Soc., Perkin Trans. 1 1993, 1019.
(13) Preparation of this naphthol will be reported elswhere.
(14) An ortho-nitrated product, 7-hydroxy-2-methyl-6-nitrobenzo[b]-
furan,11 was formed in 11% yield as an additional product: yellow
needles (from ethyl acetate-hexane); mp 124-126 °C; IR (cm-1) 3422;
1H NMR (CDCl3) δ 2.56 (d, 3H, J ) 1.0 Hz), 6.47 (q, 1H, J ) 1.0 Hz),
7.03 (d, 1H, J ) 8.8 Hz), 7.94 (d, 1H, J ) 8.8 Hz), 11.18 (s, 1H). Anal.
Calcd for C9H7NO4: C, 55.96; H, 3.65; N, 7.25. Found: C, 56.04; H,
3.42; N, 7.12.
(10) Klopman, G. In Chemical Reactivity and Reaction Paths;
Klopman, G., Eds; J ohn Wiley: New York, 1974; pp 81-82.

2776 J . Org. Chem., Vol. 61, No. 8, 1996
Ta ble 2. Nitr osa tion of Va r iou s P h en olic Su bstr a tes u n d er Ba sic Con d ition s (Meth od B)
Ishikawa et al.
not blocked.15 Phenols activated by an EDG react faster
than phenols deactivated by an EWG. Under the latter
conditions, the successful reactions were limited to phe-
nols in which the carbonyl function is located at the ortho
position of the OH group. The reaction also proceeded
smoothly in bicyclic fused phenolic systems.
pot operation without isolating the nitrosated products
as described.4
Although diazo coupling results in a C-N bond in
phenols under basic conditions, the basic nitrosation
reaction is, to our knowledge, the first example of a
practical C-N bond formed in phenols by direct electro-
philic aromatic substitution under mildly basic condition.
Therefore, the reaction described here should provide a
promising synthetic procedure for the regioselective
preparation of p-quinone monooximes and their ethers
from phenols.17
The 1H NMR spectra of p-quinone monooximes derived
from bicyclic phenolic compounds were occasionally
complex. Products from the 2-aryl-1-naphthol (Table 2,
run 16) and the benzofuran (Table 2, run 18) were
composed of E and Z isomers in a ratio of 4:1 and 6:1,
respectively. On the other hand, the products from
1-naphthol (6) itself (Table 1, run 2), the 3-aryl-1-
naphthol (Table 2, run 17), the coumarin (Table 2, run
19), and the quinoline16 (Table 2, run 21) were single
isomers. Thus, the ratio of geometric isomers in the
product should depend upon their structural features.
Futhermore, the corresponding oxime ethers were
produced in high yield by successive alkylation in a one-
An tivir a l Activity. We tested the antiviral activities
of some nitrosated products against HSV-1, HSV-2, and
HIV-1. Acyclovir (ACV) was used as a control in the HSV
(16) A simple signal pattern due to a single product was observed
in the 1H NMR spectrum when the crude quinone monooxime was
purified by silica gel column chromatography (see the Experimental
Section), whereas the product obtained by either recrystallization or
alumina column chromatography showed the presence of a pair of
geometrical isomers in a ratio of 3:1 under the same conditions: 1H
NMR (DMSO-d6) δ 6.15 (d, 3/4 × 1H, J ) 9.8 Hz), 6.42 (d, 1/4 × 1H,
J ) 9.8 Hz), 7.19 (d, 3/4 × 1H, J ) 9.8 Hz), 7.52 (dd, 1/4 × 1H, J ) 8.5,
4.2 Hz), 7.54 (dd, 3/4 × 1H, J ) 8.5, 4.2 Hz), 8.19 (d, 1/4 × 1H, J ) 9.8
Hz), 8.60 (dd, 1/4 × 1H, J ) 4.2, 1.7 Hz), 8.62 (dd, 3/4 × 1H, J ) 4.2,
1.7 Hz), 9.29 (dd, 3/4 × 1H, J ) 8.5, 1.7 Hz), 9.83 (dd, 1/4 × 1H, J )
8.5, 1.7 Hz).
(15) Nonphenolic substrates such as 1,3-dimethoxybenzene or N,N-
diethylaniline were not nitrosated. Furthermore, a trial for nitration
using isoamyl nitrate (i-AmNO3), instead of i-AmNO2, under the
conditions of basic nitrosation resulted in complete recovery of the
starting material.

Preparation of p-Quinoline Monooximes
J . Org. Chem., Vol. 61, No. 8, 1996 2777
Ta ble 3. An tivir a l Activities of Som e Nitr osa ted P r od u cts
system,18 and dideoxyinosine (DDI) and azidothymidine
(AZT) were used in the HIV system.19 Although the
antiviral assay was done in a single experiment, highly
reproducible results are obtained in plaque reduction
assay for the former system and indirect immunofluo-
rescence assay for the latter system compared to the
other method, e.g., the cytopathic effect method, in our
experience (Table 3). Two p-quinone monooximes derived
from 3-methoxyphenol (Table 3, run 1) and 8-hydrox-
yquinoline (Table 3, run 10) showed moderate activity
against HSV-1. The latter oxime was also effective
against HSV-2.
DDI against HIV-1 was shown by a simple p-quinone
monooxime derived from methyl salicylate (Table 3, run
3) and p-quinone monooximes with a fused ring system
such as naphthalene (Table 3, run 6), benzofuran (Table
3, run 8), and coumarin (Table 3, run 9) skeletons.
A comparison between both nitrosated products from
1-naphthol (Table 3, runs 6 and 7) indicated that a
p-quinone monoxime structure is more crucial than a
nitroso form for anti HIV-1 activity because of the
inactivity of 2-nitrosated 1-naphthol. We found that a
natural 1,4-naphthoquinone derivative has moderate
activities against HSV-1 and HSV-2, but none against
HIV-1.20 These findings support the notion that the
partial oxime moiety of 1,4-naphthoquinone monooxime
plays an important role in anti-HIV-1 activity. In addi-
tion, the planarity of a compound may be an alternative
factor in anti-HIV-1 activity because bicyclic quinone
monooximes were usually effective.
These anti HSV-active quinone monooximes were
inactive against HIV-1. Activity comparable to that of
(17) The Baudisch reaction, in which a chelate structure could
govern the orientation of substitution, is used for the regioselective
introduction of a nitroso group into the ortho position of the OH group
in phenols. (a) Cronheim, G. J . Org. Chem. 1947, 12, 7. (b) Cone, M.
C.; Melville, C. R.; Carney, J . R.; Gore, M. P.; Gould, S. J . Tetrahedron
1995, 51, 3095.
Thus, a p-quinone monooxime structure may be a
fundamental unit for antiviral activities, and more planar
(18) Nishiya, Y.; Yamamoto, N.; Yamada, Y.; Daitoku, T.; Ichikawa,
Y.-I.; Takahashi, K. J . Antibiot. 1989, 42, 1854.
(19) Hoshino, H.; Shimizu, N.; Shimada, N.; Takita, T.; Takeuchi,
T. J . Antibiot. 1987, 40, 1077.
(20) Ishikawa, T.; Kotake, K.-I.; Ishii, H. Chem. Pharm. Bull. 1995,
43, 1039.

2778 J . Org. Chem., Vol. 61, No. 8, 1996
Ishikawa et al.
from hexane gave slightly green needles: mp 93-96 °C (lit.23
mp 89-90 °C).
bicyclic p-quinone monooximes may be potent anti-HIV-1
agents.
On 4-Meth oxysa licyla ld eh yd e: 2-Meth oxy-5-for m yl-
1,4-ben zoqu in on e 1-Oxim e (Ta ble 2, Ru n 9). Column
chromatography using CHCl3-MeOH (10:1) gave a labile dark
red amorphous mass: IR (cm-1) 3432, 1711, 1655; 1H NMR
(CDCl3) δ 4.30 (s, 3H), 6.74 (s, 1H), 6.75 (s, 1H), 9.76 (s, 1H),
11.91 (s, 1H); HRFABMS calcd for C8H8NO4 182.0453, found
182.0454.
Exp er im en ta l Section
Gen er a l. Melting points are uncorrected. IR spectra were
obtained in Nujol. 1H (500 MHz) and 13C (125 MHz) NMR
spectra were recorded with tetramethylsilane as the internal
reference. Columns for chromatography contained silica gel
60 (70-230 mesh ASTM; Merck), and TLC proceeded on silica
gel GF254 (Merck). In general, the extract was washed with
brine, dried over magnesium sulfate, and filtered. The filtrate
was evaporated to dryness under reduced pressure. Acidic
nitrosation (method A) proceeded as described.6
Gen er a l P r oced u r e for Ba sic Nitr osa tion of P h en ols
(Meth od B). As described previously,4 i-AmNO2 (1.2-1.4
equiv) was added to a stirred 0.1 M solution of a phenol (1
equiv) in DMF in the presence of K2CO3 (1.5-2.6 equiv) at 0
°C under argon. The reaction mixture was stirred at room
temperature until the starting material disappeared on TLC
and then diluted with water and extracted with ethyl acetate.
Recrystallization of the crude product from an appropriate
solvent gave a p-quinone monooxime. The products were also
separated or purified by means of column chromatography.
On 3-Meth oxyp h en ol (3) (Ta ble 1, Ru n 1). Column
chromatography using ethyl acetate-hexane (1:1) afforded two
products. (a ) 5-Meth oxy-2-n itr osop h en ol (4): a less polar
component; reddish brown needles; mp 152-156 °C dec (lit.6
mp 153-154 °C). (b) 2-Meth oxy-1,4-ben zoqu in on e 1-oxim e
(5): a more polar component; reddish brown needles; mp 183-
185 °C dec (lit.21 mp 174 °C).
On 1-Na p h th ol (6) (Ta ble 1, Ru n 2). Column chroma-
tography using ethyl acetate-hexane (1:1) afforded two prod-
ucts. (a ) 2-Nitr oso-1-n a p h th ol (7): a more polar component;
reddish brown needles; mp 155-160 °C dec (lit.3 mp 142-146
°C); 1H NMR (CDCl3) δ 6.90 (d, 1H, J ) 9.8 Hz), 6.96 (d, 5/9 ×
1H, J ) 9.8 Hz), 7.25 (d, 4/9 × 1H, J ) 9.8 Hz), 7.36 (d, 4/9 ×
1H, J ) 7.8 Hz), 7.41 (t, 4/9 × 1H, J ) 7.8 Hz), 7.47 (d, 5/9 ×
1H, J ) 7.8 Hz), 7.49 (dt, 5/9 × 1H, J ) 7.8, 1.2 Hz), 7.59 (t,
4/9 × 1H, J ) 7.8 Hz), 7.72 (dt, 5/9 × 1H, J ) 7.8, 1.2 Hz),
8.20 (d, 4/9 × 1H, J ) 7.8 Hz), 8.35 (dd, 5/9 × 1H, J ) 7.8, 1.2
Hz). (b) 1,4-Na p h th oqu in on e 1-oxim e (8): a less polar
component; light brown needles; mp 206-208 °C dec (lit.3 mp
197 °C); 1H NMR (CDCl3 + CD3OD) δ 6.63 (d, 1H, J ) 10 Hz),
7.53 (ddd, 1H, J ) 8.7, 7.2, 1.4 Hz), 7.63 (ddd, 1H, J ) 8.7,
7.2, 1.4 Hz), 8.03 (d, 1H, J ) 10 Hz), 8.15 (dd, 1H, J ) 7.2, 1.4
Hz), 8.23 (dd, 1H, J ) 7.2, 1.4 Hz).
On Meth yl 4-Meth ylsa licyla te: 5-(Meth oxyca r bon yl)-
2-m eth yl-1,4-ben zoqu in on e 1-Mon ooxim e (Ta ble 2, Ru n
10). Recrystallization from EtOH gave slightly green
needles: mp 90-93 °C; IR (cm-1) 3163, 1685; 1H NMR (CDCl3)
δ 3.28 (s, 3H), 3.96 (s, 3H), 7.04 (s, 1H), 7.05 (s, 1H), 11.37 (s,
1H); 13C NMR (CDCl3) δ 18.12, 52.80, 109.55, 111.97, 119.84,
150.10, 161.43, 166.87, 170.71. Anal. Calcd for C9H5NO4: C,
55.39; H, 4.65; N, 7.18. Found: C, 55.38; H, 4.44; N, 7.15.
On 4-Meth oxyph en ol: 4-Meth oxy-2-n itr oph en ol (Table
2, Ru n 14). Column chromatography using ethyl acetate-
hexane (1:4) gave yellow needles: mp 69-71 °C (lit.24 mp 80
1
°C); IR (cm-1) 3234; H NMR (CDCl3) δ 3.83 (s, 3H), 7.09 (d,
1H, J ) 9.0 Hz), 7.22 (dd, 1H, J ) 9.0, 3.1 Hz), 7.51 (d, 1H, J
) 3.1 Hz), 10.35 (s, 1H). Anal. Calcd for C7H7NO4: C, 49.71;
H, 4.17; N, 8.28. Found: C, 49.51; H, 4.06; N, 8.00.
On 7-Hyd r oxy-2-m eth ylben zo[b]fu r a n :25 2-Meth yl-4,7-
ben zo[b]fu r a n oqu in on e 4-Oxim e (Ta ble 2, Ru n 18). Re-
crystallization from ethyl acetate-hexane gave dark red
1
prisms: mp 195-198 °C dec; IR (cm-1) 3162, 1626; H NMR
(DMSO-d6) δ 2.44 (s, 1/7 × 3H), 2.45 (s, 6/7 × 3H), 6.41 (d, 1/7
× 1H, J ) 10.2 Hz), 6.45 (d, 6/7 × 1H, J ) 10.2 Hz), 6.68 (s,
1/7 × 1H), 7.01 (s, 6/7 × 1H), 7.28 (d, 6/7 × 1H, J ) 10.2 Hz),
7.65 (d, 1/7 × 1H, J ) 10.2 Hz). Anal. Calcd for C9H7NO3:
C, 61.02; H, 3.98; N, 7.91. Found: C, 60.73; H, 3.80; N, 7.76.
On 8-H yd r oxycou m a r in :26 5,8-Cou m a r in oq u in on e
5-Oxim e (Ta ble 2, Ru n 19). Recrystallization from ethyl
acetate-hexane gave red prisms: mp 258-262 °C dec; IR
(cm-1) 3170, 3088, 1693, 1649; 1H NMR (DMSO-d6) δ 6.68 (d,
1H, J ) 10.0 Hz), 6.76 (d, 1H, J ) 10.0 Hz), 7.85 (d, J ) 10.0
Hz), 8.16 (d, 1H, J ) 10.0 Hz); 13C NMR (DMSO-d6) δ 118.51,
120.91, 123.39, 130.68, 138.21, 144.37, 147.13, 158.71, 176.76.
Anal. Calcd for C9H5NO4: C, 56.55; H, 2.64; N, 7.33. Found:
C, 56.65; H, 2.49; N, 7.17.
On
8-H yd r oxyq u in olin e:
5,8-Qu in olin oq u in on e
5-Oxim e (Ta ble 2, Ru n 21). After completion of the reaction
the DMF was evaporated under reduced pressure. The crude
product was purified by silica gel column chromatography with
MeOH to give brown prisms: mp > 300 °C; IR (cm-1) 1658;
1H NMR (DMSO-d6) δ 6.66 (d, 1H, J ) 10.0 Hz), 7.73 (dd, 1H,
J ) 8.0, 4.4 Hz), 7.82 (d, 1H, J ) 10.0, Hz), 8.80 (br d, 1H, J
) 10.0 Hz), 8.88 (dd, 1H, J ) 4.4, 1.3 Hz); HRFABMS calcd
for C9H7N2O2 175.0508, found 175.0501. Anal. Calcd for
C9H6N2O2‚1/10H2O: C, 61.43; H, 3.55; N, 15.92. Found: C,
61.31; H, 3.51; N, 15.59.
P r ep a r a tion of p-Qu in on e Mon ooxim e Meth yl Eth er s.
As described previously,4 i-AmNO2 (1.2 equiv) was added to a
stirred 0.1 M solution of a phenol (1 equiv) in DMF in the
presence of K2CO3 (5-10 equiv) at 0 °C under argon. After
the reaction mixture was stirred at room temperature until
the starting material disappeared from TLC, dimethyl sulfate
(Me2SO4) (1.1-1.4 equiv) was added at 0 °C, then the mixture
was stirred at the same temperature for 1 h. After decomposi-
tion of the excess Me2SO4, p-quinone monooxime methyl ethers
were purified by either recrystallization or column chroma-
tography.
On P h en ol: 1,4-Ben zoqu in on e 1-Oxim e (Ta ble 2, Ru n
1). Recrystallization from ethyl acetate-hexane gave reddish
brown needles: mp 140-143 °C (softened at 130 °C) dec (lit.22
mp 126-128 °C).
On 2-Meth oxyp h en ol: 3-Meth oxy-1,4-ben zoqu in on e
1-Oxim e (Ta ble 2, Ru n 2). Recrystallization from ethyl
acetate-hexane gave reddish brown prisms: mp 179-181 °C
(lit.22 mp 176-177 °C).
On o-Cr esol: 3-Met h yl-1,4-b en zoq u in on e 1-Oxim e
(Ta b le 2, R u n 4). Recrystallization from ethyl acetate-
hexane gave orange prisms: mp 138-140 °C dec (lit.22 mp
134-135 °C).
On
2-Ch lor op h en ol:
3-Ch lor o-1,4-b en zoq u in on e
1-Oxim e (Ta ble 2, Ru n 5). Recrystallization from ethyl
acetate-hexane gave reddish needles: mp 143-146 °C dec
(lit.22 mp 147-148 °C).
On Sa licyla ld eh yd e:
3-F or m yl-1,4-b en zoq u in on e
On 2-(Ben zyloxy)p h en ol: 3-(Ben zyloxy)-1,4-b en zo-
qu in on e 1-Oxim e Meth yl Eth er (Ta ble 2, Ru n 3). Recrys-
1-Oxim e (Ta ble 2, Ru n 6). Recrystallization from ethyl
acetate-hexane gave labile reddish brown prisms: mp 110-
114 °C (softened at 102 °C) dec; IR (cm-1) 3160, 1661; 1H NMR
(CDCl3) δ 7.11 (d, 1H, J ) 9.0 Hz), 7.78 (d, 1H, J ) 9.0 Hz),
8.61 (s, 1H), 10.14 (s, 1H), 11.80 (s, 1H); HRMS calcd for C7H5-
NO3 151.0269, found 151.0255.
(23) Houben, J .; Schreiber, G. Ber. 1920, 53, 2352.
(24) Halfpenny, E.; Robinson, P. L. J . Chem. Soc. 1952, 939.
(25) The starting benzofuran was prepared by three successive
reactions of the propargyl etherification of 2-(benzyloxy)phenol, the
cesium-mediated Claisen rearrangement (Ishii, H.; Ishikawa, T.; Ueki,
S.; Takeda, S.; Suzuki, M. Chem. Pharm. Bull. 1992, 40, 1123), and
deprotection of the benzyl group by hydrogenolysis. Ishikawa, T.;
Watanabe, T.; Oku, Y.; Takami, A. Unpublished results.
On Meth yl Sa licyla te: 3-(Meth oxylca r bon yl)-1,4-ben -
zoqu in on e 1-Oxim e (Ta ble 2, Ru n 7). Recrystallization
(21) Uffmann, H. Z. Naturforsch. 1967, 22, 491.
(22) Norris, R. K.; Sternhell, S. Aust. J . Chem. 1969, 22, 935.
(26) Harayama, T.; Katsuno, K.; Nishioka, H.; Fujii, M.; Nishida,
Y.; Ishii, H.; Kaneko, Y. Heterocycles 1994, 39, 613.

Preparation of p-Quinoline Monooximes
J . Org. Chem., Vol. 61, No. 8, 1996 2779
tallization from ethyl acetate-hexane gave reddish brown
needles: mp 99-101 °C; IR (cm-1) 3364, 3048; 1H NMR
(CDCl3) δ 4.15 (s, 3H), 5.06 (s, 2H), 6.52 (d, 1H, J ) 9.8 Hz),
6.78 (d, 1H, J ) 2.5 Hz), 7.10 (dd, 1H, J ) 9.8, 2.5 Hz), 7.32-
7.43 (m, 5H). Anal. Calcd for C14H13NO3: C, 69.12; H, 5.39;
N, 5.76. Found: C, 68.78; H, 5.33; N, 5.67.
crystallization from CH2Cl2-hexane gave yellow prisms: mp
1
232-236 °C; IR (cm-1) 1636; H NMR (CDCl3) δ 2.47 (s, 3H),
4.03 (s, 3H), 4.05 (s, 3H), 6.13 (s, 2H), 6.36 (s, 1H), 6.67 (s,
1H), 6.78 (d, 1H, J ) 8.3 Hz), 7.20 (d, 1H, J ) 8.3 Hz), 7.71 (s,
1H), 8.39 (s, 1H). Anal. Calcd for C22H17NO6: C, 67.52; H,
4.38; N, 3.58. Found: C, 67.16; H, 4.17; N, 3.46.
On
2-[4-(7-Met h oxy-2-m et h ylb en zo[b]fu r a n yl)]-6,7-
(m eth ylen ed ioxy)-1-n a p h th ol: 3-[4-(7-Meth oxy-2-m eth yl-
b e n zo[b]fu r a n yl)]-6,7-(m e t h yle n e d ioxy)-1,4-n a p h t h o-
qu in on e 1-Oxim e Met h yl E t h er (Ta b le 2, R u n 16).
Recrystallization from MeOH-CHCl3 gave reddish brown
needles: mp 264-266 °C; IR (cm-1) 1641; 1H NMR (CDCl3) δ
2.47 (s, 3H), 4.04 (s, 3H), 4.19 (s, 4/5 × 3H), 4.27 (s, 1/5 × 3H),
6.09 (s, 4/5 × 2H), 6.13 (s, 1/5 × 2H), 6.33 (s, 1H), 6.79 (d, 1H,
J ) 8.3 Hz), 7.25 (d, 1H, J ) 8.3 Hz), 7.34 (s, 1/5 × 1H), 7.63
(s, 4/5 × 1H), 7.65 (s, 4/5 × 1H), 7.79 (s, 1/5 × 1H), 7.90 (s, 4/5
× 1H), 8.42 (s, 1/5 × 1H); HRFABMS calcd for C22H18NO6
392.1134, found 392.1125. Anal. Calcd for C22H17NO6‚
1/10CHCl3: C, 65.81; H, 4.27; N, 3.47. Found: C, 66.19; H,
4.18; N, 3.37.
Ack n ow led gm en t. We thank Mr. Toshiaki Saito,
Showa College of Pharmacy, for the MO calculation. We
also thank Dr. Takemitsu Nagahata and Ryuji Ikeda
of Nippon Kayaku Co., Ltd., for assessing the antiviral
activities.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra of all compounds and 13C NMR spectra of nitrosated
products of 3-methoxyphenol, 1-naphthol, methyl salicylate,
methyl 4-methylsalicylate, and 8-hydroxycoumarin (27 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering informaton.
On
3-[4-(7-Met h oxy-2-m et h ylb en zo[b]fu r a n yl)]-6,7-
(m eth ylen ed ioxy)-1-n a p h th ol: 2-[4-(7-Meth oxy-2-m eth -
ylb en zo[b]fu r a n yl)]-6,7-(m et h ylen ed ioxy)-1,4-n a p h t h o-
qu in on e 1-Oxim e Meth yl Eth er (Ta ble 2, Ru n 17). Re-
J O951873S