The synthesis and nucleophilic substitution of haloxanthones

Article abstract of DOI:10.1002/jhet.5570380311

Acylation reaction of m-cresol with 2,6-dihalobenzoic acid in the presence of methansulfonic acid and subsequently, cyclization of the obtained o-hydroxybenzophenones with K₂CO₃/dimethyl formamide, afforded haloxanthones 4 and 5 in h

Full text of DOI:10.1002/jhet.5570380311

May-Jun 2001
The Synthesis and Nucleophilic Substitution of Haloxanthones
617
Hashem Sharghi* and Fatemeh Tamaddon
Department of Chemistry, Faculty of Science, Shiraz University, Shiraz 71454, I.R. Iran
Received January 3, 2000
Acylation reaction of m-cresol with 2,6-dihalobenzoic acid in the presence of methansulfonic acid and
subsequently, cyclization of the obtained o-hydroxybenzophenones with K CO /dimethyl formamide,
2
3
afforded haloxanthones 4 and 5 in high yields. Aromatic nucleophilic substitution of the resulted haloxan-
thones with O-, N- and S-nucleophiles are studied in a comparative manner, and various new O-, N- and
S-substituted xanthones have obtained.
J. Heterocyclic Chem., 38, 617 (2001).
Introduction.
and fluoro substituted xanthones 4 and 5 in a comparative
manner (Scheme 1).
Xanthones are one of the most important natural occuring
compounds. Beside a wide variety of chemical and indus-
trial applications, synthetic derivatives of xanthones as well
as naturally occuring derivatives have been used for medical
purposes [1-7]. The biological and photochemical behav-
iour of this family of xanthone derivatives made these sub-
stances attractive for synthetic studies [8,9].
Nucleophilic substitution of aromatic halo groups has
attracted increasing attention in recent years for both theo-
retical [10] and synthetic reasons [11-15]. Possibility to
run such reactions in dipolar media in high concentrations
with short reaction times and excellent yields has
prompted their introduction into industrial processes [16].
However, the functions are displaced by nucleophiles in
Results and Discussion
Acylation reaction of m-cresol (2) with 2,6-dihaloben-
zoic acid was carried out in anhydrous methansulfonic
acid and benzophenones 3a and 3b were obtained in 60%
and 70% yields respectively. Among the various reported
methods for cyclization of o,o'-halohydroxybenzophe-
nones [22-27] which we tried, none of them were success-
ful, and in all cases a mixture of unreacted benzophenone
and haloxanthone were obtained. In order to improve the
yields and purity of haloxanthone, we refluxed the ben-
zophenone 3 in dimethyl formamide (DMF) with K CO
and 1-halo-6-methylxanthone 4 (X = F)and 5 (X = Cl)
were obtained in quantitative yields.
2
3
dipolar aprotic solvents [11-15]. The S Ar reaction pro-
N
Generally, in direct nucleophilic aromatic substitution,
fluorides are anticipated to be the most reactive halide, and
substitution of the chloro groups requires more vigorous
conditions [11,12,28,29]. However, reaction of xanthone 4
(X = F) with sodium methoxide in methanol produced the
new 1-methoxy-6-methylxanthone (6) in 95% yield,
whereas chloro substituted xanthone 5 (X = Cl) gave the
same product in 40% yield. When the latter reaction was
carried out in DMF, the yield was increased to 65%, and
the use of Cu(1) [14,15] as a catalyst, did not improve the
reaction time and yield.
ceeds with decreasing facility in the series of F, NO >> Cl
2
> Br > I, so that for practical purposes, bromine and iodine
displacement are lacking in synthetic utility [17].
Recently, nucleophilic aromatic substitution of some nitro
derivatives of benzophenones and xanthones were studied
in dipolar aprotic solvents [18-21]. To the best of our
knowledge, there is no report about direct nucleophilic
substitution of the corresponding halo derivatives. In this
paper we report our preliminary results concerning the
nucleophilic aromatic substitution of the two new chloro
-
4) X = F
6) Nu = - OMe
5) X = Cl
7) Nu- = - OEt
8) Nu- = - OPr
9) Nu- = - O(CH CH O) H
2
2
2
10) Nu- = -NHCH CH NH
2
2
2
-
11) Nu = -NH(CH CH NH) H
2
2
2

618
H. Sharghi and F. Tamaddon
Vol. 38
The use of pyridine and deimthyl sulfoxide (DMSO)
type hydroxyldenitration reaction proceeding through an
anion-radical (copper in pyridine, potassium cyanide in
DMSO are used). In most cases the 4-hydroxy-2,2',4'-
trinitrobenzophenone is formed in approximately equal
amount (15-38%). Therefore, in an attempt to find a short
route to the new substituted xanthones 6-8, the nucleo-
philic substitution of halobenzophenones 3a and 3b were
studied.
Although, cyclization of dihalohydroxy benzophenones
is a more favorable intramolecular nucleophilic substitu-
tion and restricted to non or less nucleophilic bases, both
intra and intermolecular nucleophilic substitution may
occur. Thus, reaction of benzophenone 3a with nucle-
ophilic bases such as sodium in methanol, ethanol and
propanol produced preferentially alkoxy substituted xan-
thones 6-8 and no substituted benzophenones were
obtained (Scheme 3). A similar but slower reaction with
alkoxides occurred for chloro substituted benzophenone
3b. In both cases, the reactions with nucleophiles were not
completed and a mixture of unreacted benzophenone
together with substituted xanthone were identified. In the
case of benzophenone 3b, chloroxanthone 5 was also
obtained in addition to the above mentioned compounds
(Table 1). When nucleophilic reactions were carried out in
DMF, all yields were increased in about 10%.
were not found to be superior solvents than DMF, though
reaction of xanthone 5 (X = Cl) with sodium methoxide in
pyridine or DMSO, afforded compound 6 in 68 and 55%
yields respectively. Similarly, reaction of xanthone 4 (X =
F) with sodium in ethanol or propanol afforded xanthones
7 and 8 in 95 and 85% yields respectively, while xanthone
5 (X = Cl) reacted with sodium ethoxide or sodium
propoxide in DMF to produced new compounds 7 and 8 in
65 and 60% yields respectively.
Subsequently, reaction of xanthone 4 with sodium and
diethylene glycol in DMF afforded new xanthone 9 with
an ethylenoxy side chain in 92% yield, while reaction of
chloroxanthone 5 under similar conditions produced xan-
thone 9 in 80% yield, and an enhancement of the yield was
observed for nuucleophilic substitution of the chloro group
by diethylene glycol. As well as 1-chloroanthraquinone
[11,12,30,31], the chloro group of xanthone 5 is more
readily substituted by diethylene glycol than the simple
aliphatic alcohols. This enhancement in the rate of substi-
tuation reaction of 5 may result from nucleophilicity
enhancement of diethylene glycol by either complexation
of the cation with nucleophile, or a self-solvation process
which deaggregates the alloxide [12,31].
Reaction of xanthone 4 with ethylenediamine or diethyl-
enetriamine in DMF afforded 1-[(2-aminoethyl)amino]-6-
methylxanthone (10) or 1-[2-(2-aminoethyl)aminoethyl-
amino]-6-methylxanthone (11) in 88 and 92% yields
respectively. Compound 11 was also obtained from
chloroxanthone 5 under the above mentioned conditions in
65% yield, but refluxing of compound 5 and diethylenetri-
However, the yield and rate of chloro-displacement by
nucleophiles was lower than the flouro-displacement,
therefore, cyclization and nucleophilic substitution of ben-
Scheme 3
amine with K CO in DMF, produced xanthone 11 in
2
3
quantitative yield.
When xanthone 4 was refluxed with Na S [32] or
2
sodium thioxanthate in DMF, di(6-methylxanthono) sul-
fide (12) was obtained in 45 and 60% yields respectively
(Scheme 2).
3a) X = F
3b) X = Cl
6) R = Me
7) R = Et
8) R = Pr
In 1979 Gorvin [21] found that 3,6-dinitroxanthone is
produced from 2,2',4,4'-tetranitro benzophenone by a vari-
ety of reagents, either by an ionic route, (in the presence of
Table 1
Reaction of Halobenzophenones with some Alkoxides
-
-
OH or ONO in DMSO), or by what appears to be a Nef-
Benzophenone Conditions
Time
(h)
Product(s)
(%)
Yield
(%)
3a
3b
3a
3b
3a
3b
3a
3b
3b
3b
3b
3a
Na/MeOH/reflux
Na/MeOH/reflux
Na/EtOH/reflux
Na/EtOH/reflux
Na/PrOH/reflux
5
10
6
10
8
6
70
50
60
55
55
55
80
70
65
55
60
70
5(20)/6(30)
7
5(25/)7(30)
8
Na/PrOH/reflux
10
5
5(30)/8(25)
NaOMe/DMF/reflux
NaOMe/DMF/reflux
NaOMe/DMF/Cu
NaOMe/DMSO/Cu
NaOMe/Pyridine/Cu
NaOEt/DMF
6
10
10
10
10
6
5(30)/6(40)
6
6
6
7

May-Jun 2001
The Synthesis and Nucleophilic Substitution of Haloxanthones
619
Preparation of Halo Substituted Benzophenones 3a and 3b
General Procedure.
zophenone 3b was re-examined in the presence of copper
powder [17,18,21]. The copper assisted nucleophilic reac-
tion involves a mechanism in which halogen displacement
usually proceeds with decreasing rate of the reaction in the
series I>Br>Cl>>F. Reaction of benzophenone 3b with
sodium methoxide in DMF in the presence of copper pow-
der produced 1-methoxy-6-methylxanthone 6 in 65%
yield. The same reactions in DMSO or pyridine afforded
compound 6 in 55 and 60% yields respectively (Table 1).
It is remarkable that, the presence of copper powder did
not affect the reaction of fluorobenzophenone 3a with
sodium alkoxides, so that compounds 6 and 7 were
obtained in 80 and 70% yields from the reaction of 3a with
sodium methoxide or ethoxide in DMF respectively. An
increase of the yields (~20%) was also observed in the
copper-assisted reaction of 3b with sodium ethoxide and
propyloxide in DMF.
The preferential formation of alkoxy substituted xan-
thones during the reaction of benzophenones 3a and 3b
with alkoxides, suggests that firstly an intramolecular dis-
placement of one halo group occurred and the correspond-
ing haloxanthones were produced. Then, these haloxan-
thones undergo a subsequent intermolecular nucleophilic
substitution with alkoxides to give the alkoxy substituted
xanthones 6-8.
To a well stirring solution of anhydrous methansulfonic acid (3
ml) were added halo substituted benzoic acid (0.01 mole) and
m-cresol (0.01 mole, 1.08 g), and heated at 120 °C for 8 hours.
Then the mixture was added to crushed ice (400 g) and the benzo-
phenone was isolated either by filtration, or by extraction with
CHCl (3 × 100 ml). In the latter cases, the organic layer was
3
washed with 10% sodium bicarbonate (3 × 50 ml), water (2 × 100
ml) and brine (50 ml), dried over Na SO and evaporated under
2
4
reduced pressure to give benzophenones 3a and 3b.
2,6-Difluoro-2'-hydroxy-4'-methylbenzophenone (3a).
Compound 3a was obtained by following the general proce-
dure with 2,6-difluorobenzoic acid and m-cresol in 60% yield as
white solids; mp 100-103 °C (from ethanol 60%); R 0.85
f =
(CCl /MeOH-95:5); IR(KBr): 3300-2700(b, OH), 1645(s, C=O),
4
1610, 1580 (s,Ar), 1490(m), 1310(s), 1250(s), 1030(s), 800
-1
1
cm (s); H NMR (DMSO-d , 250 MHz): δ 2.32 (s,3H, -CH ),
6
3
6.75 (d, 1H, J = 8.14 Hz, H-5'), 6.85 (s, 1H, H-3'), 7.25 (td, 2H,
J
8.59 Hz, J 2.64 Hz, H-3 + H-5), 7.39 (d, 1H, J = 8.10 Hz,
1 =
2 =
13
H-6'), 7.68 (m, 1H, H-4),11.07 (s,1H, OH); C NMR (DMSO-
d , 62.89 MHz): δ 21.77, 112.56, 118.84, 119.60, 121.38, 132.16,
6
133.18, 149.19, 156.82, 160.89, 190.78. UV(MeOH) λ
+
236(ε =11000), 267 nm (ε=8000); MS:m/z(EI) =248 (M ,43),
max
247(20), 229(76), 228(28), 141(52), 135(100, base peak),
134(24), 113(33), 99(13), 77(57%).
Anal Calcd. for C
H O F : C, 67.74; H, 4.03. Found C,
14 10 2 2
67.63; H, 3.92.
Conclusion.
2,6-Dichloro-2'-hydroxy-4'-methylbenzophenone (3b).
In conclusion, we have found that methanesulfonic acid
offers a convenient method for synthesis of halo substi-
tuted benzophenones which are easily converted into the
Compound 3b was obtained by following the general proce-
dure with 2,6-dichlorobenzoic acid and m-cresol in 70% yield as
white solids; mp 131-133 °C (from ethanol 60%); R
f =
halo substituted xanthones in the presence of K CO in
2
3
0.8(CCl /MeOH-95:5); IR(KBr): 3200-2800 (b,OH), 1640(s,
4
DMF. Nucleophilic aromatic substitution of these halox-
anthones afforded a range of new substituted heterocyclic
compounds in high yield and purity which are not avail-
able through other synthetic methods. In addition, the sim-
plicity and convenience of this procedure make this new
method a highly useful technique in organic synthesis.
C=O), 1595, 1575(s,Ar), 1480(m), 1335(s), 1230(m), 1020(w),
-1
1
800 cm (s); H NMR (DMSO-d , 250 MHz): δ 2.35(s, 3H,
6
-CH ), 6.74(d, 1H, J = 8.2 Hz, H-5'), 6.86 (s, 1H, H-3'), 7.27 (t,
3
1H, J = 8.1 Hz, H-4), 7.57 (m, 3H, H-3+H-5+H-6'), 11.14 (s,1H,
13
OH); C NMR(DMSO-d , 62.89 MHz): δ 21.86, 118.00,
6
118.38, 121.60, 128.74, 130.68, 131.99, 137.72, 149.47, 161.61,
194.61; UV(MeOH) λ 271 nm(ε =10000); MS:m/z (EI) =283
max
+
+
(M +2, 30), 281(M ,22), 280(20), 247(30), 246(12), 245(100,
base peak), 210(48), 209(10), 175(8), 173(15), 153(8), 152(10),
135(82), 107(26), 77(70%).
EXPERIMENTAL
Solvents, reagents, and chemicals were obtained from Merck
and Fluka chemical companies. Melting points were determined
in open capillary tubes in a Buchi 510 circulating oil melting
point apparatus and are uncorrected. IR spectra were recorded on
Anal. Calcd. for C
59.94; H, 3.85.
H O Cl : C, 59.79; H, 3.56. Found C,
14 10 2 2
1-Fluoro-6-methylxanthone (4).
A mixture of benzophenone 3a (248 mg, 1 mmol) and k CO
1
a Perkin Elmer 781 spectrophotometer. H NMR spectra were
2
3
obtained on a Bruker Advance DPX FT 250 MHz, Jeol-EX 90Q
(FT 90 MHz) and Hitachi R-245 (60 MHz) for solutions in
CDCl or DMSO-d with tetramethylsilane as internal standard.
(138 mg, 1 mmol) in DMF (10 ml) was refluxed for 1 hour. Then
water (100 ml) was added and the product was extracted by
CHCl (3 × 50 ml). The organic layer washed with 10% sodium
3
6
3
Mass spectra (MS) were obtained by a GCMS-QP 1000 EX at 20
and/or 70 ev. UV spectra were recorded on a UV/Vis spectrome-
ter PU 8750. TLC were carried out on silica gel 60F-254 analyt-
ical sheets obtained from Merck chemical company. Column
chromatography was carried out on the short column of silica gel
60 mesh in glass columns using 15-30 g of silica gel per one gram
of crude mixture. Elemental analyses were performed at the
National Oil Co. of Iran at Tehran Research Center.
bicarbonate (3 × 50 ml) and water (3 × 50 ml), dried over Na SO
2
4
and evaporated to give a white solid in 98% yield; mp 125-126
°C (from ethanol 70%); R = 0.7 (CCl /MeOH-95:5); IR(KBr):
f
4
1670(s, C=O, γ-pyrone), 1610(s, Ar), 1480 (s), 1420(m),
-1
1
1305(m), 1250(w), 1180(w), 1050(s), 800 cm ; H NMR
(DMSO-d , 250 MHz): δ 2.38 (s, 3H, -CH ), 7.14 (m, 2H, H-2 +
6
3
H-7), 7.23 (s, 1H, H-5), 7.33 (d, 1H, J = 8.5 Hz, H-4), 7.40 (m,
13
1H, H-3), 7.88 (d, 1H, J = 8.1 Hz, H-8); C NMR (DMSO-d ,
6

620
H. Sharghi and F. Tamaddon
Vol. 38
62.89 MHz): δ 21.6, 111.1, 111.4, 114.4, 117.6, 119.6, 125.8,
160.5, 174.8; UV(MeOH) λ 234 (ε =10000), 280(ε=5000),
max
+
+
126.1, 135.7, 146.9, 155.0, 156.7, 158.7, 163.5, 174.0;
345 nm(ε=3000); MS:m/z (EI) =241(M +1, 12), 240(M ,60),
211(48), 194(35), 181(20), 149(17), 135(10), 121(12), 111(20),
97(31), 81(100, base peak), 73(4%).
UV(MeOH) λ 237(ε =10000), 266(ε=6000), 335 nm(ε=300);
max
+
MS: m/z ( EI ) = 228 (M , 100, base peak), 213(13), 209(15),
199(54), 170(15), 140(45), 135(26), 134(17), 113(15), 100(17),
99(15), 76(18%).
Anal. Calcd. for C H O : C, 75.0; H, 5.0. Found C, 74.7; H, 5.2.
15 12
3
1-Ethoxy-6-methylxanthone (7).
Anal. Calcd. for C H O F: C, 73.68; H, 3.95. Found C, 73.50;
14
9 2
Compound 7 was prepared by following the general procedures
A with ethanol or sodium ethoxide, within 5 or 8 hours, in 95%
yield from 4; white needles (acetone/petroleum ether); mp 116-
118 °C; R 0.4 (CCl /MeOH-95:5); IR(KBr): 2840(w, alkyl),
H, 4.16.
1-Chloro-6-methylxanthone (5).
Compound 5 was prepared from chlorosubstituted benzophe-
none 3b by following the above mentioned procedure within
2 hours and isolated by similar work up in 97% yield; White
plates (from CH Cl /light petroleum ether or EtOH 79%); mp
f =
4
1670(s,C=O, γ-pyrone), 1610, 1600(s,Ar), 1480(m), 1460(m),
-1
1
1420(w), 1280(m), 1090(s), 800 cm (s); H NMR (DMSO-d ,
6
250 MHz): δ 1.42 (t, 3H, J = 6.6 Hz, CH -CH ), 2.43 (s, 3H, Ar-
2
3
2
2
CH ), 4.14 (q, 2H, J = 6.7 Hz, -OCH -), 6.93 (d, 1H, J = 7.9 Hz,
139-140 °C; R 0.72 (CCl /MeOH-95:5); IR(KBr): 1665(s,
3
2
f =
4
H-2 or H-4), 7.07 (d, 1H, J = 8.1 Hz, H-4 or H-2), 7.21 (d, 1H, J =
7.7 Hz, H-7), 7.31 (s, 1H, H-5), 7.66 (t, 1H, J = 8.0 Hz, H-3), 7.95
C=O, γ-pyrone), 1610, 1600(s, Ar), 1450(s), 1320(m), 1240(w),
-1
1
1180(m), 900(w), 800 cm (s); H NMR (DMSO-d , 250 MHz):
6
13
(d, 1H, = 7.9 Hz, H-8); C NMR (DMSO-d , 62.89 MHz): δ
δ 2.40(s, 3H, -CH ), 7.17(d, 1H, J = 8.1 Hz, H-7), 7.25(s, 1H,
6
3
14.9, 21.6, 64.8, 107.5, 109.7, 112.1, 117.4, 120.5, 125.7, 126.1,
H-5), 7.40(d, 1H, J = 7.8 Hz, H-4), 7.49(d, 1H, J = 8.5 Hz, H-2),
13
135.6, 145.9, 154.7, 157.7, 159.8, 174.7; UV(MeOH) λ
7.69(t, 1H, J = 7.7 Hz,H-3), 7.9(d, 1H, J = 8.0 Hz, H-8);
C
234(ε =11000), 280(ε=5700), 345 nm(ε=3500); MS:m/z (EI)
NMR (DMSO-d , 62.89 MHz): δ 21.7, 117.5, 118.0, 118.2,
max
6
+
+
=255(M +1, 10), 254(M , 51), 239(100, base peak), 235(20),
226(50), 211(35), 210(47), 198(18), 197(19), 181(30), 169(18),
141(20), 115(40), 91(18), 75(22%).
119.7, 126.1, 126.2, 127.3, 132.9, 134.9, 146.8, 154.6, 157.4,
174.6; UV(MeOH) λ 239 (ε =9500), 270(ε=5000), 340 nm
max
+
+
(ε=3500); MS:m/z (EI) = 247 (M +2, 30), 245(M , 100, base
peak), 211(10), 210(50), 173(12), 152(10), 145(10), 135(82),
109(15), 107(26), 85(9), 81(9), 77(68%).
Anal Calcd. for C
H O : C, 75.6; H, 5.5. Found C, 75.45; H,
16 14 3
5.6.
Anal. Calcd. for C H O Cl: C, 68.57; H, 3.67. Found C,
68.40; H, 3.45.
14
9 2
1-Propoxy-6-methylxanthone (8).
Compound 8 was prepared by following the general procedure
A with propanol or sodium propoxide, within 8 or 10 hours, in
85% yield from 4; white needles (acetone/petroleum ether); mp
Nucleophilic Substitution of Haloxanthones 4 and 5.
Preparation of Alkoxyxanthones (6-8).
112-115 °C; R 0.5 (CCl /MeOH-95:5); IR(KBr): 2830(w,
f =
4
General Procedure A: By F-Displacement.
alkyl), 1670(s, C=O, γ-pyrone), 1610, 1600(s,Ar), 1470(s),
1420(w), 1290(m), 1270(m), 1110(w), 1090(s), 900(w), 800
To a well stirring solution of sodium (100 mg, 4 mmol) in
alcohol (10 ml) was added xanthone 4 or benzophenone 3a
(0.001 mol) and heated at reflux temperature. The cold reaction
mixture was poured onto crushed ice (100 g) and extracted with
chloroform (3 × 50 ml). The organic layer was washed with
water (2 x 50 ml) and brine (50 ml), dried over Na SO and
evaporated to give the corresponding alkoxysubstituted xan-
thones 6-8 in good yields.
-1
1
cm (s); H NMR (DMSO-d , 250 MHz): δ 1.08 (t, 3H, J = 7.20
6
Hz, -CH CH ), 1.79 (q, 2H, J = 6.38 Hz, -CH -CH ), 2.42 (s,
2
3
2
3
3H, Ar-CH ), 4.03 (t, 2H, J = 5.76 Hz, -O-CH -), 6.92 (d, J =
3
2
8.04 Hz, 1H, H-2 or H-4), 7.07 (d, 1H, J = 8.24 Hz, H-4 or H-2),
7.20 (d, 1H, J = 7.73 Hz, H-7), 7.66(t, 1H, J = 8.26 Hz, H-3),
2
4
13
7.96 (d, 1H, J = 7.95 Hz, H-8); C NMR (DMSO-d ): δ 21.6,
6
22.4, 70.4, 107.3, 109.7, 112.1, 117.4. 120.6, 125.7, 126.1, 135.6,
145.9, 154.8, 157.7, 160.0, 174.8; UV(MeOH) λ 234
General Procedure B: By Cl-Displacement.
(ε =9500), 281(ε=4500), 344 nm(ε=3500); MS:m/z (EI)=268
max
+
(M ,14), 240(20), 239(100, base peak), 225(50), 210(40),
A mixture of xanthone 5 or benzophenone 3b (0.001 mol) and
sodium alkoxide (0.01 mol) in dry DMF (10 ml) was refluxed.
Then the reaction mixture was added to crushed ice (100 g) and the
product was isolated the same as above (Scheme 1 and Table 1).
197(29), 181(10), 169(25), 141(10), 115(33), 91(12), 75(10%).
Anal. Calcd. for C
H O : C, 76.1; H, 5.97. Found C, 75.9;
17 16 3
H, 5.56.
1-[2-(2-Hydroxyethoxy) ethoxy]-6-methylxanthone (9).
1-Methoxy-6-methylxanthone (6).
To a stirring solution of sodium (0.1 g, 4 mmol) in diethylene
glycol (2 ml) was added xanthone 4 (95 mmol) in DMF (10 ml),
and the reaction mixture was heated at 120 °C for 2 hours. Then
water (200 ml) and HCl (1 ml, 0.5 M) was added and the product
was extracted with ethyl acetate (3 × 100 ml). The organic layer
was washed with water (2 × 50 ml) and brine (50 ml), dried over
Na SO and evaporated to give compound 9 in 92% yield. Viscous
Compound 6 was prepared by following the general procedure
A with methanol or sodium methoxide, within 5 hours, in 95%
yield from 4; white needles (acetone/petroleum ether); mp 116-
121 °C; R 0.32 (CCl /MeOH-95:5); IR(KBr): 2850(w, alkyl),
f =
4
1660 (s, C=O, γ-pyrone), 1610, 1600(s,Ar), 1480(s), 1300(m),
-1
1280(m), 1260(m), 1180(w), 1100(s), 950(m), 900(w), 800 cm
1
(s); H NMR (DMSO-d , 250 MHz): δ 2.40 (s, 3H, Me), 3.89
(s,3H, O-CH ), 6.94 (d, 1H, J = 7.9 Hz, H-2 or H-4), 7.6(d, 1H, J
2
4
6
oil; R 0.27(CCl4/MeOH-90:10); IR(KBr): 2850(w,alkyl),
f =
3
1650(s, C=O, γ-pyrone), 1610(s,Ar), 1490(m), 1460(s), 1360(w),
= 8.1 Hz, H-4 or H-2), 7.18(d, 1H, J = 7.8 Hz, H-7), 7.28(s, 1H,
H-5), 7.68(t, 1H, J = 8.0 Hz, H-3), 7.93(d, 1H, J = 7.8 Hz, H-8);
1320(s), 1270(m), 1220(9s), 1150(s), 1030(s), 870(s), 780(m), 760
-1
1
13
cm (s); H NMR (CDCl , 250 MHz): δ 2.50 (s,3H,Me), 3.22 (br
C NMR (DMSO-d , 62.89 MHz): δ 21.6, 56.5, 106.6, 109. 9,
3
6
s,1H, OH), 3.82 (t, J = 7.5 Hz, 4H, -CH -O-CH -) 4.06 (t,J = 7.5
111.9, 117.3, 120.6, 125.7, 126.1, 135.6, 145.9, 154.7, 157.6,
2
2 ,

May-Jun 2001
The Synthesis and Nucleophilic Substitution of Haloxanthones
621
Hz, 2H, -CH -OH), 4.24 (t, J = 7.5 Hz, 2H, ArO-CH2-), 6.78
mole of compound 5, K CO (0.005 mole) and diethylenetri-
2 3
2
(s,1H), 7.03 (d,J = 7.5 Hz, 1H), 7.17 (d, J = 7.5 Hz, 1H), 7.35 (d,
J = 7.5 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 8.16 (d, J = 7.5 Hz, 1H);
amine (0.05 mole) in DMF or DMSO (10 ml) within 2-3 hours
produced xanthone 11 in quantitative yield which isolated as the
same above.
UV(MeOH) λ 233 (ε =10000), 278(ε=4500), 343 nm(ε=3000);
max
+
+
MS:m/z (EI)=315(M +H , 100, base peak), 314(M+, 28), 299(31),
268(5), 252(25), 239(23), 226(54), 198(20), 181(18), 168(16),
153(23), 115(37), 107(40), 91(42), 76(60%).
Di(6-methylxanthono) Sulfide (12).
To a stirring solution of haloxanthone 4 (1 mmol) in DMF
(10 ml) was added sodium thioxanthate (5 mmol, 0.67 g) and
heated under reflux for 5 hours. Then water (100 ml) was added
and the precipitate was isolated by filtration to give compound
Anal. Calcd. for C
H O : C, 68.79; H, 5.7. Found C, 69.1;
18 18 5
H, 5.36.
1-[(2-Aminoethyl)amino]-6-methylxanthone (10).
12 in 60% yield; pale yellow plates; mp 220-222 °C (dec.); R =
f
0.75(CCl /MeOH-90:10); IR(KBr): 1660(s, C=O, γ-pyrone),
A stirring mixture of fluoroxanthone 4 (5 mmol), and ethylene-
diamine (0.05 mol) in DMF (10 ml) was refluxed for 3 hours.
Then water (200 ml) was added and the precipitate was filtered
off to give compound 10 in 88% yield; recrystallized from ace-
tone/n-hexane as shiny yellow needles; mp 155-156 °C (dec.);
4
1615, 1585(s,Ar), 1450(s), 1350(m), 1320(m), 1290(m),
-1
1
1160(w), 1120(w), 950(s), 870(s), 780 cm (s);
H
NMR(CDCl , 250 MHz): δ 2.5 (s, 6H, 2 x Me), 7.10 (d, J = 7.5
3
Hz, 2H, 2 × H-4), 7.28 (d, J = 7.5 Hz, 2H, 2 × H-7), 7.4 (s,2H,
2 × H-5), 7.54 (d, J = 7.5 Hz, 2H, 2 × H-2), 7.65 (t, J = 7 Hz,
R = 0.32 (CH Cl /MeOH-80:20); IR(KBr): 3600 (s, NH),
f
2
2
13
2H, 2 × H-3), 8.01 (d, J = 7.5 Hz, 1H, 2 × H-8);
C
3320(d,NH ), 2910, 2870(w,alkyl), 1630(s,H-bonded C=O,
2
NMR(DMSO-d , 62.89 MHz): δ 21.7, 117.4, 117.6, 119.7,
120.0, 126.2, 127.8, 134.9, 146.9, 155.0, 157.6, 174.8;
γ-pyrone), 1595(s,Ar), 1550(s), 1470(w), 1280(s), 1230(s),
6
-1
1170(s), 1120(m), 1080(s), 940(s), 870(s), 790(s), 760 cm (s);
1
UV(MeOH) λ 210(ε =8500), 335 nm(ε=2000); MS: m/z
H NMR (CDCl , 250 MHz): δ 1.49 (br t ,2H, exchange NH ),
max
3
2
+
+
+
(EI)=452(M +2,12), 451(M + 1,35), 450(M , 100, base peak),
435(20), 433(8), 418(20), 316(13), 300(5), 242(40), 241(95),
226(10), 225(20), 210(18), 209(17), 181(11), 152(20), 115(8),
97(15), 83(25), 77(11), 73(11%).
2.49 (s, 3H, Me), 3.05 (t, J = 7.5 Hz, 2H, -CH -NH ), 3.36 (dt,
2
2
J = 7.5 Hz, J = 5 Hz, 2H, NH-CH -), 6.40 (d, J = 7.5 Hz, 1H,
1
2
2
H-2 or H-4), 6.65 (d, J = 7.5 Hz, 1H, H-4 or H-2), 7.21 (d, J =
7.5 Hz, 1H, H-7), 7.39 (t, J = 7.5 Hz, 1H, H-3), 7.7 (s, 1H, H-5),
8.3 (d, J = 7.5 Hz, 1H, H-8), 9.67 (br s, 1H, exchange NH Ar);
Anal. Calcd. for C
H O S: C, 74.66; H, 4. Found C, 74.21;
28 18 4
13
C NMR (DMSO-d , 62.89 MHz): δ 21.7, 45.7, 101.9, 104.4,
H, 3.86.
6
106.1, 117.3, 119.5, 125.6, 125.7, 136.6, 146.1, 151.8, 155.1,
Similarly, reaction of holoxanthone 4 or 5 (0.001 mol) with
157.7, 178.8; UV(MeOH) λ 233(ε =112200), 268(ε=6000),
Na S (0.1 g) in DMF (10 ml) within 5 or 8 hours produced sul-
fide 12 in 45 and 30% yields respectively, which was isolated as
the same above work up.
max
2
+
305(ε=2000), 404 nm (ε=3000); MS: m/z (EI)=268(M , 10),
251(10), 239(24), 238(100, base peak), 225(5), 210(25), 181(11),
123(5), 91(5), 76(5%).
Acknowledgement.
Anal. Calcd. for C
H N O : C, 71.64; H, 5.97. Found C,
16 16 2 2
71.8; H, 5.63.
Partial support of this work by Shiraz University Research
Council and Professor N. Iranpoor for his helpful comments is
gratefully acknowledged.
1-[2-(2-Aminoethyl)aminoethylamino]-6-methylxanthone (11).
A stirring mixture of fluoroxanthone 4 (5 mmole), and diethyl-
enetriamine (0.05 mole) in DMF (10 ml) was refluxed for
2 hours. Then water (200 ml) was added and the precipitate was
isolated by filtration to give compound 11 in ~95% yield; recrys-
tallized from acetone/n-hexane as yellow needles; mp 110-111 °C
REFERENCES AND NOTES
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2
1600, 1585(s, Ar), 1520(w), 1450(m), 1420(m), 1290(m),
-1
1
1230(m), 1180(m), 1030(w), 950(m), 800 cm (s); H NMR
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3
2
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13
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+
+
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239(73), 238(100, base peak), 225(6), 210(18), 181(9), 153(6),
115(37), 85(5), 73(36%).
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H N O : C, 69.45; H, 6.75. Found C,
18 21 3 2
69.15; H, 6.59.
Compound 11 was also obtained from chloroxanthone 5 under
above mentioned conditions in 65% yield, but refluxing of 0.005
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