Synthesis of 4-methyl pyrrolo[2,3-b]-xanthone, a novel ring system

Article abstract of DOI:10.1080/00397910500214383

A short, high yielding synthesis of a novel substituted pyrrolo[2,3-b]-xanthone has been developed. The synthesis begins with a copper catalyzed Ullmann coupling reaction followed by and intramolecular Friedel-Crafts acylation reaction to establish the xa

Full text of DOI:10.1080/00397910500214383

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Synthesis of 4‐Methyl
Pyrrolo[2,3‐b]xanthone, a
Novel Ring System
Samuel E. Watson a
a Department of Chemistry and Biochemistry , Long
Island University , Brooklyn, New York, USA
Published online: 22 Aug 2006.
To cite this article: Samuel E. Watson (2005) Synthesis of 4‐Methyl
Pyrrolo[2,3‐b]xanthone, a Novel Ring System, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 35:20,
2695-2701
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Synthetic Communicationsw, 35: 2695–2701, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500214383
Synthesis of 4-Methyl Pyrrolo[2,3-b]-
xanthone, a Novel Ring System
Samuel E. Watson
Department of Chemistry and Biochemistry, Long Island University,
Brooklyn, New York, USA
Abstract: A short, high yielding synthesis of a novel substituted pyrrolo[2,3-b]-
xanthone has been developed. The synthesis begins with a copper catalyzed
Ullmann coupling reaction followed by and intramolecular Friedel-Crafts acylation
reaction to establish the xanthone core structure. After a regioselective nitration, a
Leimgruber-Batcho synthesis establishes the final pyrrole ring.
Keywords: Ullman coupling reaction, pyrrolo[2,3-b]xanthone, Leimgruber-Batcho
synthesis
It has been found that substituted pyrrolo[2,3-b]xanthones, novel ring systems,
have interesting biological activity. To explore this activity and in preparation
for further biological testing, a succinct synthesis of the model system
4-methyl-pyrrolo[2,3-b]xanthone 1 (Figure 1) has been developed from
readily available starting materials and is easily amenable to scaling and so
can provide multigram amounts.
From a retrosynthetic point of view, it was decided to build the ring
system in a stepwise fashion as shown in Scheme 1. It was believed that the
well-established two-step Leimgruber–Batcho indole synthesis[1] would be
a good procedure for synthesizing the pyrrole ring from the known
3,4-dimethyl-2-nitroxanthone 2 (xanthone numbering).[2] This compound
can be made by nitrating 3,4-dimethylxanthone, which is itself obtained in
Received in the USA May 18, 2005
Address correspondence to Samuel E. Watson, Department of Chemistry and
Biochemistry, Long Island University, Brooklyn Campus, Brooklyn, NY 11202,
USA. E-mail: swatson@liu.edu
2695

2696
S. E. Watson
Figure 1. 4-Methyl-pyrrolo[2,3-b]xanthone.
two steps from the commercially available 2-chlorobenzoic acid 3 and 2,3-
dimethylphenol 4 by means of the well-known Ullmann reaction followed
by an acid-catalyzed intramolecular Friedel–Crafts acylation reaction.[2,3]
There have been many reports in the literature on the synthesis of substi-
tuted xanthones.[4] Among the most widely used[2,3] is the two-step sequence,
first introduced by Goldberg and Walker,[5] based on the initial copper
catalyzed Ullmann coupling of a 2-halobenzoic acid with a substituted
phenol followed by Friedel–Crafts cyclodehydration as shown in Scheme 2.
The first step was accomplished using the conditions described by Frahm
and Pickert.[2] 2-Chlorobenzoic acid was heated neat in the presence of an
excess of 2,3-dimethylphenol and potassium carbonate along with a
catalytic amount of cuprous iodide and copper bronze. Yields for this trans-
formation, as noted in the literature,[6] were variable. The reaction is
extremely moisture and air sensitive. When freshly purified cuprous iodide
and freshly activated copper bronze[7] were used under strictly anhydrous
conditions and under an inert atmosphere, yields of up to 45% after recrystal-
lization were obtained, along with varying amounts of diaryl compounds.
(Copper iodide was purified by precipitation from potassium iodide [13.15 g
CuI dissolved in a solution made of 130 g of KI in 100 mL of distilled
water] and dried over phosphorus pentoxide at 1008C for two days.)
Under less rigorously anhydrous and inert conditions, the reaction failed
completely.
A variety of other methods and conditions were attempted to improve the
throughput of the first step. Rewcastle et al.[3] report high yields of coupled
product when the preformed sodium salts of the 2-chlorobenzoic acid and
an ortho-substituted phenol were heated in the presence of cuprous chloride
and tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1) as the phase-transfer
catalyst in boiling dioxane as described by Soula.[6g] In our hands, yields on
Scheme 1.

4-Methyl Pyrrolo[2,3-b]xanthone
2697
Scheme 2.
the order of 10% were obtained even after much experimentation. Similarly,
the procedure of Tomita[8] as described in detail by Evans and Ellman,[6h]
using anhydrous potassium carbonate and copper oxide in freshly distilled
pyridine under strictly anhydrous conditions, failed to give more than small
amounts of the desired benzoic ether 5. It is known that ortho-substitution
on the phenol hinders the reaction.
The dehydrative ring-closure step could be affected by using either 80%
sulfuric acid[3] or using polyphosphoric acid (PPA).[2] The latter reagent gave
virtually quantitative yields of 3,4-dimethylxanthone 6. The product was
generally clean enough to be used directly in the nitration step.
Nitration of 3,4-dimethylxanthone 6 using standard conditions gave
primarily mono-nitration at the desired 2-position but also some nitration at
the 7-position in amounts of up to 30–35% as judged by proton NMR
spectra of the crude reaction mixtures (Scheme 3). Control of the temperature
was found to be critical. If the temperature was kept below 2108C during the
slow addition of the nitrating agent, yields of up to 90% of the desired isomer
could be obtained. The isomers could be separated by silica gel chromato-
graphy but the overall recovery was low because of the limited solubility of
the nitro-xanthone. Because only the desired isomer would react in the two-
step pyrrole-forming sequence, the mixed material was carried onto the
pyrrole ring-forming step.
The crude nitration mixture was heated in dimethylformamide in the
presence of an excess of dimethylformamide dimtheylacetal (DMFA) and
pyrrolidine (Scheme 3). In 1 h the starting material was consumed and
replaced by a mixture of enamines 8. These brick-red solids were collected
by precipitation from a mixture of ice-cold ethyl acetate and hexane (1 : 5)
after removal of the volatiles under reduced pressure. It should be noted
Scheme 3.

2698
S. E. Watson
that use of the pyrrolidine as an auxiliary base as described by Leimgruber and
Batcho in their original article was critical to the success of this transforma-
tion. Without pyrrolidine, the reaction was not complete even after 24 h at
1008C as judged by thin-layer chromatography and there was a considerable
amount of dark, baseline material produced, indicative of decomposition.
The enamine was too unstable to be chromatographed on silica gel or
alumina but the crude reaction mixture obtained by removal of the volatiles
under reduced pressure could be crystallized from a mixture of ethyl acetate
and hexane. The resulting brick-red solid was dissolved in a one-to-one
mixture of methanol and tetrahydrofuran and subjected to catalytic hydroge-
nation at 08C and one atmosphere of pressure. The reaction was usually
complete in 2–3 h. Filtration and removal of solvents gave the crude
pyrrolo-xanthone 1 as a yellow solid in good yields. Recrystallization from
a 1 : 3 mixture of tetrahydrofuran and methanol gave clean material, judged
1
to be more than 95% pure by H and 13C NMR.
In summary we have developed a short route to the novel 4-methyl-
pyrrolo[2,3-b]xanthone 1 that is amenable to scaling and to the synthesis of
a variety of substituted derivatives. Further work is under way on
improving the consistency and overall yields of the Ullmann coupling step.
EXPERIMENTAL
1
All NMR spectra were recorded on a 400-MHz spectrometer. H and 13C
spectra are reported as chemical shift values (ppm) with reference to TMS
as the internal standard. Mass data were obtained using the FAB technique
at Washington University, Mass Spectrometry resource. Infrared spectra
were obtained on a Nicolet Magna 760 FTIR. Melting points were determined
with a Mel-Temp II melting-point apparatus in open capillary tubes and are
uncorrected. All solvents were distilled and stored over molecular sieves.
Air-sensitive reactions were carried out under a nitrogen atmosphere.
2-(2,3-Dimethylphenoxy)benzoic acid 5. 2-Chlorobenzoic acid (15.7 g,
100 mmol), potassium carbonate (14.0 g, 100 mmol), freshly activated
copper bronze[8] (0.1 g), and freshly purified copper iodide[7] were ground
in a mortar and added to a dry 500-mL round-bottomed flask containing a
magnetic stir bar and equipped with two water-cooled condensing columns
joined in sequence under an atmosphere of nitrogen. 2,3-Dimethylphenol
(24.43 g, 200 mmol) was added and the reaction mixture was heated slowly
to 2008C in an oil bath in the presence of a Teflon-coated magnetic stir bar
with a magnetic stirrer. The reaction mixture slowly darkened and became a
homogeneous liquid at 65–708C, at which point stirring commenced.
Bubbling with gas evolution began at 130–1408C and there was a rapid
exotherm to 180–1908C. The reaction mixture was maintained at 2008C for
3 h and cooled to 80–908C, and 200 mL of 1.0 M aqueous sodium bicarbonate

4-Methyl Pyrrolo[2,3-b]xanthone
2699
was added. The solution was filtered through a pad of Celite to remove copper
salts and the filtrate was washed three times with 75-mL portions of
ethyl acetate to remove excess phenol. The aqueous layer was acidified to
pH 2–3 with concentrated hydrochloric acid and then stirred at 4–58C for
2 h. The resulting off-white solid was collected by filtration, washed with
100 mL of cold H2O, air dried, and recrystallized from ethyl acetate to give
10.9 g (45.2 mmol, 45%) as a pale solid. The spectral data agreed with litera-
1
ture values[2]: mp 178–1798C; H NMR (400 MHz, CDCl3) d 2.05 (s, 3H),
2.12 (s, 3H), 6.67 (d, 1 H, J ¼ 8.2 Hz), 6.70 (d, 1H, J ¼ 8.4 Hz, 6.96 (dd,
1H, J ¼ 8.2, 0.7 Hz), 7.08 (br, 1H, s), 7.13 (ddd, 1H, J ¼ 7.7, 7.3, 0.7 Hz),
7.43 (ddd, 1H, J ¼ 8.4, 7.3, 1.6 Hz), 7.77 (dd, 1H, J ¼ 7.7, 1.6 Hz), 11.9
(br, s, 1H); 13C NMR (CDCl3) d ¼ 15.46, 20.07, 117.74, 118.41, 122.27,
123.01, 127.49, 128.31, 131.01, 131.77, 132.72, 132.89, 151.98, 155.94,
166.58. Anal. calcd. for C15H14O3: C, 74.38; H, 5.79. Found: C, 73.69; 5.63.
3,4-Dimethylxanthone 6. 2-(2,3-Dimethylphenoxy)benzoic acid 5 (5.0 g,
20.66 mmol) was heated to 1008C in the presence of 85 g of polyphosphoric
acid with stirring for 1 h. The reaction mixture was cooled slightly; 150 mL
of water was added and stirring was continued for 30 min. The solution was
filtered and the filtrate was washed with cold water to give a light cream-
colored solid. This material was recrystallized from ethyl acetate to give
3,4-dimethylxanthone as an off-white solid (4.07 g, 18.17 mmol, 88%): mp
1
161–1628C[2]; H NMR (CDCl3) d ¼ 2.293 (s, 3H), 2.306 (s, 3H), 7.021
(d, 1H, J ¼ 8.3 Hz), 7.260 (t, 1H, J ¼ 7.6 Hz), 7.375 (d, 1H, J ¼ 8.0 Hz),
7.595 (t, 1H, J ¼ 8.0 Hz), 8.226 (d, 1H, J ¼ 7.6 Hz); 13C NMR (CDCl3)
d ¼ 10.76, 19.61, 117.20, 119.05, 120.63, 122.25, 124.05, 125.03, 125.64,
125.73, 134.73, 144.31, 153.21, 155.52, 175.83; IR (KBr) 1653, 1605,
1336, 758 cm21. Anal. calcd. for C15H12O2: C, 80.36; H, 4.96. Found: C,
80.16; H, 5.21.
3,4-Dimethyl-2-nitroxanthone 2. A mixture of ice-cold concentrated sulfuric
acid (2.50 mL) and 0.5 mL of nitric acid (70%, 10 mmol) was added slowly
dropwise to a solution of 3,4-dimethylxanthone (2.24 g, 10 mmol) dissolved
in sulfuric acid (15 mL) at 215 to 2108C. When the addition was
complete, the reaction was stirred for 15 min at 2108C, poured into 50 mL
of ice-cold water, and filtered. The resulting cream-colored filter cake was
washed twice with 15-mL portions of cold water and dried at 608C under
reduced pressure for 24 h to give an off-white powder (2.58 g, 9.6 mmol,
96%). TLC (30% ethyl acetate/hexane) indicated one major product
(Rf ¼ 0.42) as well as some starting material (Rf ¼ 0.56) and another
compound (Rf ¼ 0.36). The crude reaction mixture was of sufficient purity
to be used in the next step. An analytical sample was prepared by chromato-
graphy over silica gel, eluting with 20% ethyl acetate in hexane, and recrys-
1
tallization from ethyl acetate: mp 191–1938C; H NMR (CDCl3) d ¼ 2.42
(s, 3H), 2.51 (s, 3H), 7.511 (dd, 1H, J ¼ 8.0 and 7.3 Hz), 7.72 (d, 1H,

2700
S. E. Watson
J ¼ 9.0 Hz), 7.93 (dd, 1H, J ¼ 9.0 and 7.3 Hz), 8.21 (d, 1H, J ¼ 8.0 Hz), 8.43
(s, 1H); 13C NMR (CDCl3) d ¼ 11.91, 15.73, 118.42, 118.62, 118.90, 120.27,
124.73, 125.74, 128.94, 135.91, 137.15, 146.64, 154.83, 154, 83, 175.23;
IR (KBr) 2894, 1652, 1605, 1531, 1322, 1240, 760 cm21. Anal. calcd. for
C15H12O2: C, 80.36; H, 4.96; N, 5.20. Found: C, 80.16; H, 5.21; N, 5.03.
4-Methylpyrrolo[2,3-b]xanthone 1. Crude 3,4-dimethyl-2-nitroxanthone
(2.58 g, 9.6 mmol) was dissolved in dry dimethylformamide (15 mL), and
dimethylformamide dimethylacetal (DMFA) (3.85 mL, 28.8 mmol) and pyrro-
lidine (0.93 mL, 11.52 mmol) were added. The reaction mixture was heated
under an inert atmosphere at 1008C for 2 h. The volatiles were removed
under reduced pressure and the resulting red solid residue was dissolved in
ethyl acetate (10 mL). Hexane (30 mL) was added. The solution was stored
at 2108C for 24 h and filtered to give a brick-red solid (2.66 g, 8.16 mmol,
1
85%). H NMR indicated this material to be a mixture of the pyrrolidine
and dimethylamino enamines 8 and 9.
The crude mixture of enamines was dissolved in dry THF/MeOH (1 : 1,
30 mL) and cooled to 08C. Palladium on carbon (10%, 200 mg) was added.
The reaction mixture was degassed and stirred at 08C under one atmosphere
of hydrogen for 2 h and then allowed to warm slowly to rt. Filtaration
through celite, removal of the solvent, and recrystallization from methanol
provided compound 1 as a pale yellow solid (1.48 g, 5.95 mmol, 62% for
1
two steps): mp ¼ 268 decomp; H NMR (DMSO) d ¼ 2.642 (s, 3H), 3.30
(d, 1H, J ¼ 8.0 Hz), 6.63 (d, 1H, J ¼ 2.0 Hz), 7.355 (dd, 1H, J ¼ 7.2 Hz),
7.60 (d, 1H, J ¼ 8.0 Hz), 7.753 (m, 2H), 8.07 (s, 1H), 8.14 (d, 1H,
J ¼ 7.2 Hz); 13C NMR (CDCl3) d ¼ 12.406, 100.781, 105.880, 115.409,
117.048, 118.505, 120.568, 126.426, 132.450, 133.391, 134.559, 135.348,
136.228, 147.063, 156.410, 177.745; IR (KBr) 3232.2, 2917.52, 1621.82,
1512.99, 1474.62, 1338.18, 1159.94, 868.29, 768.52 cm21. MS (FAB) 256
(M þ Li), 160, 136, 89. HRMS m/z C15H12NO2 256.0954, found 256.0958.
Anal. calcd. for C15H12NO2: C, 80.36; H, 4.96; N, 5.20. Found: C, 80.16;
H, 5.21; N, 5.03.
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