Polyphosphoric acid-mediated, One-Pot, novel reactions to build polymethoxyarylnaphthalene lignans

Article abstract of DOI:10.1080/00397910902978023

The one-pot reaction of succinic anhydride with 1,2-dimethoxybenzene furnished two structurally complicated polymethoxyarylnaphthalene lignans, polymethoxyarylnaphthol 1 as the minor product and polymethoxynaphtho[1,2-b] oxacycloheptatrienone 2 as the major product, in the presence of a small amount of polyphosphoric acid (PPA) as catalyst at 140°C and yielded 2 as a single product in good yield when a large amount of PPA as solvent was employed at 60-80°C. The novel structures of 1 and 2 were elucidated from 1H NMR, 13C NMR, infrared (IR), and Electrospray ionization-mass spectrometry (ESI-MS) and further confirmed by X-ray diffractions. The possible mechanisms for the formation of 1 and 2 were also proposed.

Full text of DOI:10.1080/00397910902978023

Synthetic Communications1, 40: 351–360, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902978023
POLYPHOSPHORIC ACID–MEDIATED, ONE-POT,
NOVEL REACTIONS TO BUILD
POLYMETHOXYARYLNAPHTHALENE LIGNANS
Guilong Zhao,1 Fuxu Zhan,2 Zhifeng Wang,3 Weiren Xu,1
Yuli Wang,1 Wei Liu,1 Lida Tang,4 and Jianwu Wang2
1Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin
Institute of Pharmaceutical Research, Tianjin, China
2School of Chemistry and Chemical Engineering, Shandong University,
Jinan, China
3School of Chemistry and Chemical Engineering, Qufu Normal University,
Jining, China
4Tianjin State Key Laboratory of Pharmacokinetics and Pharmacodynamics,
Tianjin Institute of Pharmaceutical Research, Tianjin, China
The one-pot reaction of succinic anhydride with 1,2-dimethoxybenzene furnished two
structurally complicated polymethoxyarylnaphthalene lignans, polymethoxyarylnaphthol
1 as the minor product and polymethoxynaphtho[1,2-b]oxacycloheptatrienone 2 as the
major product, in the presence of a small amount of polyphosphoric acid (PPA) as catalyst
at 140ꢀC and yielded 2 as a single product in good yield when a large amount of PPA as
solvent was employed at 60–80ꢀC. The novel structures of 1 and 2 were elucidated from
1H NMR, 13C NMR, infrared (IR), and Electrospray ionization–mass spectrometry
(ESI-MS) and further confirmed by x-ray diffractions. The possible mechanisms for the
formation of 1 and 2 were also proposed.
Keywords: Arylnaphthalene lignan; Friedel–Crafts acylation; one pot; polyphosphoric acid; synthesis;
x-ray diffraction
INTRODUCTION
Polymethoxyarylnaphthalene lignans belong structurally to arylnaphthalene
lignans, and the latter often possess two kinds of strongly electron-donating groups,
such as methoxy groups and methylenedioxy groups. Polymethoxyarylnaphthalene
lignans constitute an important class of naturally occurring bioactive products that
possess hypocholesterolemic,[1] antirheumatic,[2] anti-HIV,[3] and antitumor[4] activi-
ties and can also be employed as apical sodium codependent bile acid transporter
Received January 5, 2009.
Address correspondence to Guilong Zhao, Tianjin Key Laboratory of Molecular Design and Drug
Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China. E-mail: zhao_guilong@
126.com and Professor Jianwu Wang, School of Chemistry and Chemical Engineering, Shandong
University, Jinan 250100, China. E-mail: jwwang@sdu.edu.cn
351

352
G. ZHAO ET AL.
Scheme 1. Reaction of 3 and 4 in the presence of PPA as catalyst at 140ꢀC to yield polymethoxyaryl-
naphthalene lignans 1 and 2.
inhibitors.[5] However, because of their nonconventional structures and the presence
of a number of sterically congested, strongly electron-donating groups in one
molecule, such as methoxy groups and=or methylenedioxy groups, the synthesis of
polymethoxyarylnaphthalene lignans and their methylenedioxy counterparts were
considerably challenging.[1–9]
During the total synthesis of 400-O-acetylmananthoside B,[10–13] unexpectedly
we found a polyphosphoric acid–mediated novel reaction of succinic anhydride 3
with 1,2-dimethoxybenzene 4 to produce two polymethoxyarylnaphthalene lignans,
polymethoxyarylnaphthol 1 as the minor product and polymethoxynaphtho[1,2-
b]oxacycloheptatrienone 2 as the major product (Scheme 1). An optimized reaction
of 3 with 4 could provide 2 specifically in good yield (Scheme 2). These two reactions
and the novel lignans 1 and 2 could find applications in the synthesis of lignans and
in the pharmaceutical field, respectively.
RESULTS AND DISCUSSION
During the total synthesis of 400-O-acetylmananthoside B, we initially designed
an intermediate 10 and envisioned that this intermediate could be prepared from
Scheme 2. Reaction of 3 and 4 with PPA as solvent at 60–80ꢀC to furnish 2 as a single product.

POLYMETHOXYARYLNAPHTHALENES
353
Scheme 3. Initially envisioned mechanism for the formation of 10 from 3 and 4.
1,2-dimethoxybenzene 3 and succinic anhydride 4 through two sequential Friedel–
Crafts acylation reactions followed by tautomerization (Scheme 3).
It was found experimentally that the reaction of 3 with 4 in the presence of a
number of Lewis acids or Brønsted acids in a variety of solvents at various tempera-
tures did not occur at all, and therefore we devised a neat reaction of them in the
presence of polyphoric acid (PPA) as catalyst. However, the reaction of 3 and 4 in
the presence of PPA at 140ꢀC furnished two products, which were isolated and ident-
ified as 1 (minor product) and 2 (major product), instead of the initially envisioned 10
(Scheme 1).
To unequivocally elucidate the structure of the two products, product 1 was
acetylated to its acetate 100 by acetic anhydride (Scheme 4). The structure of 1 was
1
elucidated from H NMR,13C NMR, infrared (IR), and Electrospray ionization–
mass spectrometry (ESI-MS) of both 1 and 100 and further confirmed by the x-ray
diffractions of 100 (Fig. 1), and the structure of 2 was determined from the spectro-
scopic methods aforementioned and also further confirmed by the x-ray diffraction
of 2 as a cocrystal of 2 and ethyl acetate (Fig. 2).
Encouraged by this interesting one-pot reaction and the novel structures of 1
and 2, in particular the potential applications of these two lignans in the pharmaceu-
tical field, we then optimized this reaction. After considerable experimentation, the
optimal reaction conditions for this reaction were as follows: (1) the molar ratio
of 3=4 ranges from 0.5–2.0, (2) the ratio of 3=4 by weight of PPA to total amounts
of 3 and 4 is 5=20, and (3) reaction temperature is 140ꢀC.
Scheme 4. Acetylation of 1 with acetic anhydride to give rise to its acetate 100.

354
G. ZHAO ET AL.
Figure 1. Crystal structure of 100.
Given that the reaction of 3 and 4 under the reaction condition described
produced two products (1 and 2) simultaneously and that the separation of them
required column chromatography, we therefore continued the optimization of this
reaction with an expectation to produce both of them specifically. After a lot of
Figure 2. Cocrystal structure of 2 with ethyl acetate.

POLYMETHOXYARYLNAPHTHALENES
355
experimentation, compound 2 could be produced individually. Thus, 3 and 4 were
heated at 60–80ꢀC with PPA as solvent to provide 2 as a single product in good yield
(Scheme 2). Nonetheless, attempts to optimize the reaction condition to furnish 1 as
a single product were unsuccessful. Parenthetically, 1 and 2 were always produced as
a mixture if a catalytic amount of PPA was employed and the reaction was carried
out at high temperatures, and the proportion of 1 in the product mixture reached up
to maximum under the optimized reaction conditions.
After structures of 1 and 2 were determined unambiguously, we commenced to
investigate the mechanisms for the formation of the two novel products and herein
propose the possible mechanisms for their formations.
Two possible mechanisms for the formation of 1, each involving two Friedel–
Crafts acylations and one Friedel–Crafts alkylation, were proposed, as represented
by path a and path b in Scheme 5. Compound 3 underwent Friedel–Crafts acylation
with 4 in the presence of PPA as catalyst to give b-benzoylpropionic acid 5. Follow-
ing path a, 5 underwent intramolecular Friedel–Crafts acylation catalyzed by PPA to
afford diketone 6, which tautomerized to form naphthalene-1,4-diol 10. In the
Scheme 5. Two possible mechanisms for the formation of 1.

356
G. ZHAO ET AL.
presence of PPA, one hydroxyl group of 10 was protonated followed by dehydration
to give rise to a transient carbocation 7, which was stabilized by two fused phenyl
rings, one hydroxyl group, and two methoxy groups, and therefore was considerably
more stable than conventional aromatic carbocations. Carbocation 7 was trapped by
another molecule of 3 to furnish 1 through Friedel–Crafts alkylation. Alternatively,
following path b, compound 3 underwent Friedel–Crafts acylation with b-benzoyl-
propionic acid 5 in the presence of PPA as catalyst to yield diacetophenone 8, which
tautomerized to give dienol 9. One hydroxyl group in 9 was protonated by PPA fol-
lowed by intramolecular dehydration to produce 1 via intramolecular Friedel–Crafts
alkylation.
The possible mechanism for the formation of 2 is proposed in Scheme 6. The
esterification of b-benzoylpropionic acid 5 with 1, both of which were already
presented in Scheme 4, was effected in the presence of PPA as catalyst to deliver ester
10, which tautomerized to give enol 11. Finally, enol 11 yielded 2 after the protona-
tion of its hydroxyl group by PPA followed by dehydration through intramolecular
Friedel–Crafts alkylation.
These two reactions may find applications in the synthesis of arylnaphthalene
lignans. The two polymethoxyarylnaphthalene lignans 1 and 2 may also find
applications in the pharmaceutical field. The investigation of the pharmacodynamic
properties of 1 and 2, along with their derivatives, is in progress.
Scheme 6. Possible mechanism for the formation of 2.

POLYMETHOXYARYLNAPHTHALENES
357
EXPERIMENTAL
Melting points were determined with an XT-4 microscopic melting-point
apparatus and are uncorrected. IR spectra were recorded on a Thermo Nicolet Avtar
1
Fourier transform (FT)–IR spectrophotometer as KBr discs. H NMR and 13C
NMR spectra were recorded on a Bruker AC300 or AC400 spectrometer at
300 MHz or 400 MHz for 1H NMR and at 75 MHz or 100 MHz for 13C NMR, with
dimethyl sulfoxide (DMSO-d6) or CDCl3 as solvent and tetramethylsilane (TMS) as
internal standard. The ESI-MS spectra were taken on an ABI API4000 system.
Elemental analyses were performed with an Elementar EI Vario EL III CHN
analyzer.
6,7-Dimethoxy-1-(3,4-dimethoxyphenyl)naphth-4-ol (1) and 5,7-Di(3,4-
dimethoxyphenyl)-2,3-dihydro-9,10-dimethoxy-1-oxanaphtho[1,2-b]-
cycloheptatrien-2-one (2)
A 250-mL, round-bottomed flask was charged with 10.0 g (72.5 mmol) of
1,2-dimethoxybenzene 3 and 10.0 g (100 mmol) of succinic anhydride 4, and the flask
was heated in an oil bath held at 140ꢀC until all the starting materials were melted to
a clear solution. In a 25-mL beaker, 3.0 g of phosphorus pentaoxide were carefully
added to 2.0 g of 85% phosphoric acid portionwise while stirring to produce freshly
prepared PPA as a viscous, colorless oil. The prepared PPA was added in one
portion to the molten materials, and the resultant mixture was stirred at 140ꢀC
for 3 h.
On slight cooling, 50 mL of acetone was added with care to the reaction flask
and the stirring was continued for 15 min to give a purple solution. This solution was
poured into 300 mL of ice water, and the aqueous mixture thus obtained was
brought to pH 14 with concentrated aqueous sodium hydroxide, warmed on a
hot-water bath until a clear purple solution formed, and then brought back to pH
4–5 with concentrated hydrochloric acid. This aqueous solution was exacted with
three 50-mL portions of DCM, and the combined exacts were washed with saturated
brine, dried over sodium sulfate, and evaporated on a rotary evaporator to afford a
residue, which was separated and purified by column chromatography to furnish 1
and 2 as white solids.
Compound 1, white solid, mp 198–200ꢀC, 3.82 g, yield 31%. IR (KBr): n 3374,
1600, 1513, 1495, 1259, 1171 cmꢁ1. 1H NMR (CDCl3, 300 MHz): d 7.55 (s, 1H), 7.24
(s, 1H), 7.11–7.13 (d, 1H, J ¼ 7.5 Hz), 6.97–7.02 (m, 3H), 6.74–6.77 (d, 1H,
J ¼ 7.8 Hz), 3.83, 3.90, 3.97, 4.05 (4 s, 3H each). 13C NMR (CDCl3, 75 MHz): d
149.83, 149.81, 148.87, 148.63, 148.02, 133.97, 131.75, 128.77, 125.19, 122.12,
119.79, 113.34, 111.18, 107.03, 105.01, 100.97, 55.95, 55.71. ESI-MS, m=z ¼ 341.4
([M þ H]þ), 358.4 ([M þ NH4]þ), 698.6 ([2 M þ NH4]þ), 703.5 ([2 M þ Na]þ).
Elemental analysis calcd. for C20H20O5: C, 70.57; H, 5.92. Found: C, 70.47; H, 5.90.
Compound 2, white solid, mp 202–204ꢀC, 6.42 g, yield 49%. IR (KBr): n 1763,
1
1621, 1510, 1465, 1258, 1246 cmꢁ1. H NMR (DMSO-d6, 400 MHz): d 7.59 (s, 1H),
7.26 (s, 1H), 7.03–7.06 (d, 1H, J ¼ 8.4 Hz), 6.99–7.00 (d, 1H, J ¼ 2.0 Hz), 6.95–6.97
(d, 1H, J ¼ 8.4 Hz), 6.957–6.962 (d, 1H, J ¼ 2.0 Hz), 6.90–6.91, 6.92–6.93 (dd, 1H,
J ¼ 2.0 Hz and 8.0 Hz), 6.92 (s, 1H), 6.858–6.862, 6.878–6.883 (dd, 1H, J ¼ 2.0 Hz

358
G. ZHAO ET AL.
and 8.2 Hz), 6.32–6.36 (t, 1H, J ¼ 7.2 Hz), 3.97, 3.78, 3.76, 3.75, 3.73, 3.72 (6 s, 3H
each), 3.20 (bs, 2H). 13C NMR (DMSO-d6, 100 MHz): d 168.93, 150.34, 149.87,
148.92, 148.60, 148.48, 148.27, 144.50, 141.33, 134.34, 131.87, 131.57, 127.43,
125.46, 122.23, 121.54, 121.41, 121.00, 119.20, 113.07, 112.01, 111.85, 111.60,
104.87, 101.46, 55.52, 55.48, 55.44, 55.31, 34.44. ESI-MS, m=z ¼ 543.4 ([M þ H]þ),
560.4 ([M þ NH4]þ), 565.4 ([M þ Na]þ), 581.3 ([M þ K]þ). Elemental analysis calcd.
for C32H30O8: C, 70.84; H, 5.57. Found: C, 70.75; H, 5.59.
Suitable crystals of 2 for x-ray single-crystal diffraction were obtained by slow
evaporation of a solution of 2 in DCM=ethyl acetate=petroleum ether at room tem-
perature. A colorless crystal of 2 with dimensions of 0.24 mm ꢂ 0.18 mm ꢂ 0.10 mm
was mounted on a glass fiber in a random orientation at 113(2) K. The determination
˚
of unit cell and data collection were performed with MoKa radiation (k ¼ 0.71073 A)
on a Bruker Smart CCD diffractometer with a w-x scan mode. A total of 10476
reflections including 5374 independent ones (Rint ¼ 0.0307) were collected in the
range of 3.24ꢀ <h < 25.02ꢀ, of which 3843 were observed [I > 2r(I)] and used in
the structure determination and refinements. The structure was solved by direct
methods with SHELXS-97 program.[14] The nonhydrogen atoms were refined
anisotropically, and the hydrogen atoms were determined with theoretical calcu-
lation. A full-matrix least-squares refinement gave R1 ¼ 0.0640, wR2 ¼ 0.1830 [w ¼
1=[r2ðFo2Þ þ (0.1138P)2 þ 0.7150P], where P ¼ ðFo2 þ 2Fc2Þ=3], S ¼ 1.099, (Dq)max
¼
1.057, and (Dq)min ¼ ꢁ 0.614 e ꢃ Aꢁ3. The crystal is triclinic, and its space group is
˚
ꢀ
˚
˚
˚
P-1, with a ¼ 11.002(2) A, b ¼ 12.141(2) A, c ¼ 12.682(3) A, a ¼ 79.04(3) ,
3
b ¼ 72.43(3) , c ¼ 73.90(3) , V ¼ 1541.1(5) A , Z ¼ 2, Dc ¼ 1.359 g ꢃ cmꢁ3, F(000) ¼
668, and m ¼ 0.099 mmꢁ1. The determined empirical formula of this crystal,
C36H30O10, with formula weight 630.66, is consistent with the cocrystal of 2 and
one molecule of ethyl acetate.
ꢀ
ꢀ
˚
6,7-Dimethoxy-1-(3,4-dimethoxyphenyl)naphth-4-ol Acetate (100)
Into a 100-mL, round-bottomed flask, 3.40 g (10 mmol) of 1, 1.00 g (12.2 mmol)
of anhydrous sodium acetate, 20 mL of acetic anhydride, and 10 mL of glacial acetic
acid were introduced, and the resulting mixture was stirred at reflux for 1 h.
On cooling, the reaction mixture was poured into 200 mL of cooled water, and
the resulting mixture was stirred at room temperature for 3 h until the complete
hydrolysis of acetic anhydride. The acidic aqueous solution thus obtained was
exacted with three 50-mL portions of DCM, and the combined extracts were washed
with saturated brine, dried over sodium sulfate, and evaporated on a rotary evapor-
ator to afford the crude product as a residue, which was purified by column chroma-
tography to yield the pure product 100 as colorless crystals. Mp 168–170ꢀC, 3.71 g,
1
yield 97%. IR (KBr): n 1756, 1485, 1512, 1605 cmꢁ1. H NMR (CDCl3, 300 MHz):
d 7.25–7.29 (m, 2H), 7.14–7.16 (m, 2H), 6.99–7.07 (m, 3H), 3.82, 3.90, 3.97, 4.02
(4 s, 3H each). 13C NMR (CDCl3, 75 MHz): d 169.61, 149.79, 148.61, 148.25, 144.83,
136.70, 133.33, 128.81, 124.95, 122.55, 122.02, 116.14, 113.11, 111.06, 105.33, 99.85,
55.92, 55.80, 55.76, 21.15. Elemental analysis calcd. for C22H22O6: C, 69.10; H, 5.80.
Found: C, 69.04; H, 5.81.
Crystals of 100 suitable for x-ray single-crystal diffraction were obtained by slow
evaporation of a solution of 100 in DCM=ethyl acetate=petroleum ether at room

POLYMETHOXYARYLNAPHTHALENES
359
temperature. A colorless crystal of 100 with dimensions of 0.24 mm ꢂ 0.18 mm ꢂ
0.10 mm was mounted on a glass fiber in a random orientation at 273(2) K. The
determination of unit cell and data collection were performed with MoKa radiation
˚
(k ¼ 0.71073 A) on a Bruker Smart CCD diffractometer with a w-x scan mode. A
total of 14060 reflections including 3271 independent ones (Rint ¼ 0.0485) were col-
lected in the range of 1.61ꢀ < h < 24.80ꢀ, of which 2049 were observed [I > 2r(I)]
and used in the structure determination and refinements. The structure was solved
by direct methods with SHELXS-97 program.[14] The nonhydrogen atoms were
refined anisotropically, and the hydrogen atoms were determined with theoretical
calculation. A full-matrix least-squares refinement gave R1 ¼ 0.0447, wR2 ¼ 0.1071
[w ¼ 1=[r2ðFo2Þ þ (0.0624P)2 þ 0.3251P], where P ¼ ðFo2 þ 2Fc2Þ=3], S ¼ 1.010,
(Dq)max ¼ 0.261, and (Dq)min ¼ ꢁ 0.210 e ꢃ Aꢁ3. The crystal is monoclinic, and its space
˚
ꢀ
˚
˚
˚
group is P21=c, with a ¼ 12.8203(3) A, b ¼ 8.3471(2) A, c ¼ 18.1518(4) A, a ¼ 90 ,
b ¼ 99.270(2) , c ¼ 90 , V ¼ 1917.10(8) A , Z ¼ 4, Dc ¼ 1.325g ꢃ cmꢁ3, F(000) ¼ 808,
and m ¼ 0.096 mmꢁ1. The determined empirical formula of this crystal, C22H22O6,
with formula weight 382.40, is consistent with the acetate of 1.
3
ꢀ
ꢀ
˚
5,7-Di(3,4-dimethoxyphenyl)-2,3-dihydro-9,10-dimethoxy-1-oxanaphtho-
[1,2-b]cycloheptatrien-2-one (2)
In a 250-mL, round-bottomed flask, 20 g of 85% phosphoric acid and 30 g of
phosphorus pentaoxide were carefully added portionwise while stirring. The result-
ing mixture was stirred to give 50 g of freshly prepared PPA as a viscous colorless oil.
Subsequently, 5.0 g (36.2 mmol) of 1,2-dimethoxybenzene 3 and 5.0 g (50 mmol) of
succinic anhydride 4 were added in one portion, and the resultant mixture was stirred
at 60–80ꢀC for 3 h.
On slight cooling, the reaction mixture was slowly poured into 400 mL of ice
water, and the mixture thus obtained was stirred for 1 h. Concentrated sodium
hydroxide was slowly added to neutralize the aqueous mixture to pH 5–7, and the
precipitate was collected via filtration with suction. The filtrate was back-exacted
with three 50-mL portions of DCM, and the combined exacted were mixed with
the collected precipitate to afford a solution, which was washed with brine, dried
over sodium sulfate, and evaporated on a rotary evaporator to furnish the product
2 as a residue. The crude product was purified by column chromatography to yield
the pure product as a white solid (5.62 g, yield 86%).
ACKNOWLEDGMENT
The authors are very grateful to Professor Jiong Jia of Shandong University for
recording of part of the NMR spectra, collecting x-ray diffraction data of one of the
two crystals (2), and discussing the work.
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¨

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Copyright of Synthetic Communications is the property of Taylor & Francis Ltd and its content may not be
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