Synthesis of Tetraoxygenated Terephthalates via a Dichloroquinone Route: Characterization of Cross-Conjugated Liebermann Betaine Intermediates

Article abstract of DOI:10.1002/hlca.201600392

Cross-conjugated quinoid betaines 4 (2,5-bis(alkoxycarbonyl)-3,6-dioxo-4-(1-pyridinium-1-yl)cyclohexa-1,4-dien-1-olates; Liebermann betaines) were synthesized from 2,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,4-dicarboxylates (2) and pyridines in acetone c

Full text of DOI:10.1002/hlca.201600392

Received Date: 20-Dec-2016
Revised Date: 16-Jan-2017
Accepted Date: 19-Jan-2017
Article Type: Full Paper
Synthesis of Tetraoxygenated Terephthalates via a Dichloroquinone
Route: Characterization of Cross-Conjugated Liebermann Betaine
Intermediates
Lukas Hintermann,*,a,b Philipp J. Altmann,a,b Panče Naumov,c and Keisuke Suzukid
a Department Chemie, Technische Universität München, Lichtenbergstraße 4, 85748 Garching bei München, Germany, +4989-289-13699,
lukas.hintermann@tum.de
b TUM Catalysis Research Center, Ernst-Otto-Fischer-Straße 1, 85748 Garching bei München, Germany
c New York University Abu Dhabi, P. O. Box 129188, Abu Dhabi, United Arab Emirates
d Department of Chemistry, Tokyo Institute of Technology, O-okayama 2-12-1, Meguro-ku, 152-8551 Tokyo, Japan
Dedicated to the memory of Hans Liebermann and David Lisser
Cross-conjugated quinoid betaines 4 (2,5-bis(alkoxycarbonyl)-3,6-dioxo-4-(1-pyridinium-1-yl)cyclohexa-1,4-dien-1-olates; Liebermann
betaines) were synthesized from 2,5-dichloro-3,6-dioxo-cyclohexa-1,4-diene-1,4-dicarboxylates (2) and pyridines in acetone containing
water. Their structure was secured by NMR spectroscopy and by X-ray diffraction analysis of 4f (alkoxy = OEt, pyridine = 4-Me2NC5H4N).
Betaines 4 show comparatively high reactivity towards nucleophiles as a consequence of their cross-conjugated character. Betaine 4a
and hydroxy-3,4-methylenedioxybenzene (sesamol) condense to give a pyridinium quinolate salt 14 which has a bifurcate hydrogen bond
from a pyridinium N+–H donor to both carbonyl (C=O) and olate (C–O–) acceptors in the solid state. Betaine 4b hydrolyzes in aqueous
solution to give diethyl 2,5-dihydroxy-3,6-dioxocyclohexa-1,4-diene-1,4-dicarboxylate (11) as a pyridinium salt, or as polymeric zinc(II)
complex of the dianion of 11 in the presence of ZnCl2. Dihydroxyquinone 11 was analytically differentiated from its independently
prepared hydroquinone form, diethyl 2,3,5,6-tetrahydroxy-terephthalate (12), by NMR analysis in solution and X-ray crystal structure
determination of both compounds.
Keywords: betaines • conjugation • nitrogen heterocycles • quinones • structure elucidation
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Introduction
The regioselective composition of fully substituted, highly oxygenated aromatic cores needs to be addressed in the total synthesis of
oxygenated natural products, a leading example being polycyclic xanthones.[1] Such challenges were presented in synthetic approaches
towards aglycon 1 of the xanthoquinone antibiotic FD-594[2][3] with its hexasubstituted aromatic D-ring with six different substituents
(Scheme 1a).
Scheme 1. a) Retrosynthetic disconnection of xanthone A to dihaloquinone terephthalate C. b) Synthesis of a tetraoxygenated terephthalate.
Based on a chirality transfer strategy already successfully implemented in total syntheses of the pradimicin, benanomicin and TAN-1085
structures,[4] FD-594 aglycon (1) was disconnected to a xanthone A (Scheme 1a). The latter reveals a hidden symmetry[5] after
disconnection to O-aryl ether B, since this compound might result from an SNAr reaction of quinone C (X = leaving group) with phenol D.
The approach took inspiration from work by Liebermann and Lisser[6] who had coupled dichloroquinone 2b with phenols in the presence of
pyridine to give derivatives of type 3 (Scheme 1b), and had proposed the mesomeric betaine 4b (Liebermann’s betaine) as isolable
reaction intermediate (Scheme 1b, Figure 1).
Figure 1. Structures of Liebermann betaines discussed in this work.
Mesomeric, heterocyclic betaines possess intriguing electronic structures that present challenges to theories of electronic structure and
systems of classification alike.[7][8] They serve as intermediates in the synthesis of aromatic and heterocyclic compounds,[7][9] and some
have been isolated from natural sources.[10] Liebermann and Lisser had reported the single representative 4b in 1934 and assigned its
structure based on indirect arguments.[6][11] While syntheses of targets corresponding to A starting from dichloroquinone esters 2 have
eventually been realized via slightly different routes,[3][12] we wish to report here the result of experiments undertaken to explore the
option of using the fascinating betaines 4 as synthetic entry into tetraoxygenated terephthalates. In the course of those studies, we have
determined spectral, structural and reactivity properties of several betaines 4 (Figure 1).
Results and Discussion
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Dichloroquinones 2 are conveniently prepared on laboratory scale from succinylosuccinates 5 and N-chlorosuccinimide in acetic acid.[13]
The analogous reaction of 5b with N-bromosuccinimide (NBS) gives bromoquinone ester 6b (Scheme 2a). However, the latter compound
results in higher yield from direct bromination of 5.[14][15] Compound 6a is likewise obtained by direct bromination of 7a, which is
conveniently prepared from 5a and NCS.[13] The last step of the multistep conversion from either 5 or 7 to 6:
is reversible; therefore, mixtures of 6 and 8 are obtained unless an excess of Br2 is applied. The reversibility of reaction (1) was proven by
heating 6b with HBr in acetic acid: bromine vapors are liberated, and 8b is isolated from the reaction mixture (Scheme 2b). However,
reference samples of dibromohydroquinones 8 are best obtained by dithionite reduction of quinones 6 (Scheme 2c).
Scheme 2. a) Br2, HOAc, r.t. (6a, 82% from 7a) or NBS, HOAc, 80 °C→ r.t. (6b, 46% from 5b). b) Na2S2O4, H2O, CH2Cl2 (8a, 94%), or HBr·HOAc, 85 °C (8b,
73%). c) NBS, HOAc, or Br2, HOAc, r.t.
According to Liebermann and Lisser, diethyl 2,5-dichloroquinone-1,4-dicarboxylate 2b reacts with excess pyridine in acetone to give dark
crystals of betaine 4b (Table 1).[6] Based on the plausible stoichiometry, this reaction consumes an equivalent of water, which may have
come either from residual water present in commercial acetone, or from water generated through a pyridine induced aldol condensation
of acetone itself. We prefer to add a few drops of water to the reaction mixture to render the precipitation of betaines more reliable. The
crude betaine crystals were often contaminated with pyridinium chloride, as indicated by a positive Ag+-test for chloride. Due to their
limited stability in protic solvents, and low solubility in most other solvents, the crude betaines could not be readily purified by
recrystallization. Specific purification protocols were thus developed, including washing sequences with ethanol or isopropanol, or
chemical removal of hydrogen chloride by stirring with Ag2O, followed by filtration, evaporation and crystallization (see experimental part
for details). Liebermann-betaines 4 derived from various chloroquinone esters 2 and pyridines were thus obtained in analytically pure
form (Table 1), except for dimethyl ester 4a, whose solubility properties prevented the isolation of the pure compound (Table 1, entry 1).
Table 1. Synthesis of Liebermann betaines.a
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entry
quinone
pyridine
product
yield [%]
1
2a (R = Me)
Py
–
4a
4b
4c
4d
2
3
4
5
2b (R = Et)
2c (R = Bn)
2d (R = Men)b
2b (R = Et)
Py
59–62
Py
53
Py
76
3,5-Me2Py
66
4e
6
2b (R = Et)
DMAP
76
4f
a See experimental part for reaction condition details. b Men = (1R)-menthyl = (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl. Py = pyridine.
Betaines 4b–d were obtained by reaction of the starting esters 2 with pyridine (Table 1, entries 2–4). Ethyl ester 3b also reacts with 3,5-
dimethylpyridine or 4-N,N-dimethylaminopyridine (DMAP) to give betaines 4e or 4f, respectively (Table 1, entries 5,6). Reactions of 2b
with quinoline, isoquinoline or 2,4-dimethylpyridine showed low conversion and gave impure reaction products, pointing to a steric
limitation of the reaction. Methyl ester betaine 4a, which is readily generated from 2a or 6a, has not been obtained free from halide salt
impurities, but its in-situ solutions could be used for further reactions (vide infra). Betaines 4 are either rust-red powders or dark violet
solids, depending on particle size. Fresh solutions in hydroxylic solvents are red, but those in aprotic solvents are intensely dark-violet.
Compound 4b crystallizes from hot acetonitrile as dark-red dendritic microcrystals. The more lipophilic menthyl ester betain 4d
crystallized from CH2Cl2–hexane, but twinning along the largest crystal face beset a structural characterization of the plate-like, thin,
dark-violet crystals. Crystals suitable for X-ray diffraction were obtained from dark-violet solutions of 4f in CH2Cl2–hexane. The
crystallographic analysis (Figure 2) confirms the structure proposed by Liebermann, which had relied on elemental analysis data and
reactivity considerations.[6] The dimethylamino-group of 4f is coplanar and fully conjugated to the heterocyclic ring, while the pyridinium
substituent itself is rotated relative to the plane of the quinoid core by 63°. The bonding angles of the exocyclic substituents around the
fully substituted six-membered quinoid core ring deviate from the idealized 120° geometry. Notably, the angle O(3)-C(5)-C(4) amounts to
125.7°, N(1)-C(2)-C(3) to 115.8°, and O(2)-C(3)-C(2) to 115.6°. While it is tempting to ascribe part of this deviation to electrostatic
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attraction between O(2) and N(1), it should be noted that the observed deviations are always directed towards the longer intra-ring C–C
bonds and thus may also represent an equilibration of steric repulsion among the exocyclic substituents. In the supramolecular structure
of 4f, four equivalent molecules meet with their ethyl end groups in the center of the unit cell, allowing for relatively large librations in
this “hydrophobic region”, hence the observed disorder. The molecules are tiled with their quinoid rings along the α-axis.
a)
b)
Figure 2. a) ORTEP representation of a single molecule of 4f with ellipsoids at the 30% probability level. Nitrogen atoms are colored blue, oxygen atoms red.
b) Unit cell view showing the center, where four ethyl groups meet in a hydrophobic, disordered region.
Betaines 4 are notably electrophilic; they slowly hydrolyze in solution in the presence of moisture. Dark-red aqueous solutions of 4b turn
brown-yellow over a day at room temperature, or within 3 h at 60 °C. Evaporation of such hydrolysates to dryness gives a brown-red
residue that is soluble in CH2Cl2 or CDCl3; its NMR data are consistent with pyridinium salt 10 of dihydroxyquinone ester 11 (Scheme 3a).
Scheme 3. Syntheses of quinone 11, hydroquinone 12 and derivatives of 11 from Liebermann's betaine 4b.
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A corresponding 1H-NMR spectrum was obtained by mixing 2,5-dihydroxyquinone 11 with pyridine in CDCl3. The latter was prepared by
dissolving chloroquinone 2b in aqueous base, followed by acidification (Scheme 3).[16] If the basic solution was treated with sodium
dithionite prior to acidification, hydroquinone ester 12 precipitated instead.[17] Both compounds had been described in the late 19th
century, but there is little recent work on them in spite of their potential relevance as ligands for metal-organic frameworks.[18] In 1989,
dimethyl tetrahydroxyterephthalate was claimed as the side-product of reactions of chloroquinone dimethylester 2a with basic
nucleophiles in DMSO,[19] but comparison of the reported 13C-NMR data with those of 11/12 shows that the compound in question must
have been the dihydroxyquinone dimethylester.1 The 1H-NMR spectrum of dihydroxyquinone 11 in CDCl3 solution displays two
broadened singlets in the high frequency region at δ 13.73 and 15.00 in a ratio of ≈12:1, which could correspond to two hydrogen-bond
tautomers like I and II (Scheme 4),2 whereas the (D6)-DMSO solution features a single signal for the OH group at δ(1H) = 9.53 that could be
hydrogen bonded to the solvent. Dynamics of 11 in CDCl3 are evident from observation of only one carbon signal (δ(13C) = 106.6, C-1/4) for
the quinoid core; the second signal for C-2/3/5/6 is presumably invisible due to line broadening. In DMSO solution, signals for both C-1/4
(110.2) and C-2/3/5/6 (163.3) are apparent; the equivalency of C-2 with C-6 and of C-3 with C-5 points to fast tautomeric exchanges via
structures III and IV.
Scheme 4. Tautomeric structures of 11.
The X-ray crystal structure for 11 shows the molecule to have a planar structure with all non-hydrogen atoms in one plane (Figure 3). Both
phenolic hydroxy groups are involved in intramolecular hydrogen bonds with ester carbonyl oxygens, representing tautomer I (cf.
Scheme 4). The quinoid carbonyl bond C(1)–O(1) is shortened to 121.5 pm, the ester carbonyl C(4)–O(3) at 123.1 pm, and the C(3)–O(2)
single bond to hydroxyl at 131.1 pm. The C–C bonds separating the conjugated 3-hydroxy-2-alken-1-one subunits C(1)–C(3a) and C(1a)–
C(3) are only slightly shorter (152.2 pm) than a regular C–C single bond.
Figure 3. ORTEP representation of dihydroxyquinone 11. Ellipsoids are shown at 50% probability.
1 The missassignment was probably caused by the observation of 4 peaks in the 13C-NMR spectrum (DMSO; δ = 52.15, 110.37, 163.77, 168.56) rather than the 5
peaks expected for a static structure. The actual symmetry is higher due to a dynamic proton exchange, vide infra.
2 The high frequency shift of the minor tautomer should be due to a salicylate type 6-membred ring hydrogen bond, and not a hydroxyquinone type 5-
membered ring H-bond; compare δ(1H) in CDCl3 of the OH-group in methyl salicylate (10.74) relative to that of 2,5-dihydroxyquinone (7.74).
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A sample solution of the tetrahydroxyphthalate 12 in CDCl3 evaporated to leave a rather large single crystal (see Figure S-1). Any
ambiguity as to whether oxidation to quinone 11 might have occurred in air was resolved when X-ray crystallography revealed the crystal
to be composed of 12. All hydroxy groups are involved in intramolecular hydrogen bonds to their proximal ester group, either to carbonyl
or alkoxy oxygen (Figure 4). The hydrogen binding to alkoxy oxygen is also involved in another hydrogen bond to a phenolic oxygen of a
neighboring molecule as acceptor.
Figure 4. Representation of two molecules of 12 showing intramolecular and intermolecular hydrogen bonding schemes. Ellipsoids are shown at 50%
probability.
Returning to the topic of hydrolysis of betaine 4b, it was found that some metal ions (Ca2+, Ag+, Mg2+, Zn2+) accelerate the process, which
is then accompanied by precipitation of metal containing solids. Among these, the Zn(II) complex 13 resulting from reaction of 4b with
excess aqueous ZnCl2 was isolated as insoluble, brown-orange powder. This material analyzed as [Zn2+(C12H10O82–)(H2O)2] and must be a
coordination polymer involving the bridging dianion of 11 as doubly chelating ligand (Scheme 3). Related complexes of 2,5-
dihydroxyquinones are known and can assume a variety of oligomeric or polymeric structures.[20] The generation of such complexes by in
situ release of the ligand through hydrolysis of a water-soluble precursor is notable. Finally, the reactivity of Liebermann’s betaines
towards phenols as nucleophiles was explored. While the reaction of dihaloquinones 2 and 6 with phenols and pyridine in acetone leads
to symmetric, doubly substituted 2,5-diaryloxyquinones,[6][15] in situ generation of betaine 4 and coupling with phenols gives access to
asymmetric mono-O-arylated quinone dicarboxylates.[6] With an intent to use this reaction towards a xanthone precursor A for the FD-
594 aglycon synthesis (Scheme 1), methyl ester betaine 4a was generated in situ from bromoquinone 6a and pyridine in acetone, and
coupled with sesamol (benzo[d][1,3]dioxol-5-ol; Scheme 5). From the non-uniform product mixture, a crystalline material could be
separated after two recrystallizations, which was identified as hydroxyquinone pyridinium-salt 14 by X-ray crystal-structure analysis
(Scheme 5).
Scheme 5. Coupling of sesamol with an in situ prepared betaine. Py = pyridine.
The pyridinium cation of 14 binds to the hydroxyquinone anion through a three-centered hydrogen bond [N(1)−H = 92.8 pm, N(1)···O(1) =
285.6 pm, N(1)−H(17)···O(1) = 119.0°; N(1)···O(3) = 270.1 pm, N(1)−H(17)···O(3) = 161.4°]. The quinone ring is essentially planar (rmsd =
0.02 Å) and inclined 75.7° to the plane of the 1,3-benzodioxol-5-yloxyl moiety. The smaller angle at the oxygen bridge C(2)–O(4)–C(11)
amounts to 120°. The methoxycarbonyl groups are rotated out of the plane of the central ring by 75.6° [C(7)–O(5)–O(4)] and 41.4° [C(10)–
O(6)–O(7)]. The larger rotation of the carboxymethyl group at C(1) is related to a stacking interaction of its π-system with the benzodioxol
moiety, possibly in a donor-acceptor fashion. The formal single bond C2−O8 (134.1 pm) is conjugated to the formal double bond C(6)–
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O(1) (121.3 pm; compare to standard C(sp2)–O and C=O values of ca. 135 and 121 pm, respectively), whereas C5−O3 (124.8(2) pm) and
C3−O2 (122.9(2) pm) are part of a fully delocalized system bearing the negative charge, which is asymmetrically distorted towards O(3).
The overall conjugated system resembles a para- rather than an ortho quinoid one. In the crystal unit cell of 14 (Fig. 4), two structurally
equivalent molecules are π-π stacked via the aromatic rings of the 1,3-benzodioxol-5-yloxyl substituents across the center-of-symmetry
(C---C = 372−377 pm). Pyridine-hydroxyquinone adducts such as 10 or 14 can take the form of either hydrogen bridged adducts or salts
with complete proton-transfer, depending on the components or the medium.[21] The full proton transfer in 14 is assisted by the
acidifying effect of the methoxycarbonyl substituents on the hydroxy-quinone.
a)
b)
Figure 5. Figure a) ORTEP representation of 14 at the 50% probability level. b) Unit cell view showing the intermolecular stacking of benzodioxole units.
Liebermann-betaines 4 are cross-conjugated heterocyclic mesomeric betaines that are isoconjugate to an odd, alternant hydrocarbon
mono-anion (class 9), according to the classification scheme of Ollis et al.[7][22] The term cross-conjugated indicates that the positive and
negative charges are delocalized into separate parts of the conjugated system, which follows from an analysis of the energetically most
plausible dipolar canonical structures. Betaines 4 can be compared to some related pyridinium-olates for further clarification (Figure 6).[23]
Ullmanns betaine (15)[24] is comparable to 4 in that the charges are mainly located in fragments that correspond to a pyridinium cation
and a 1,3-diketonate anion, but they are connected in such a way that the negative charge is also conjugated into the pyridine unit. Three
carbons bear both positive and negative charges in suitable canonic resonance structures, which means that in contrast to 4, 15 is a
conjugated mesomeric betaine. Further analysis of the dipolar canonical structures shows that it is a conjugated N-ylide, as the 1,2-polar
resonance form contributes considerably to the true molecule, and it is isoconjugate to an odd alternant hydrocarbon anion (class 5 of
Ollis et al).
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Figure 6. Selected betaines and their classifications, with major limiting structure (top) and isoconjugate hydrocarbon anions (below). The sites of
delocalization of positive (red), negative (blue) or both (purple) charges in the canonic resonance forms are also indicated in the formula below.
The case of Diels’ betaine 16[25]), which has also been identified as the alkaloid punicine from Punica granatum,[26] is interesting as it could
principally occur in two tautomeric forms 16a/b, of which 16a is a conjugated mesomeric betaine, isoconjugate to an odd alternant
hydrocarbon anion (class 1), and 16b is a cross-conjugated betaine, isoconjugate to an odd, alternant hydrocarbon monoanion (class 9).
The more recently reported betaine 17[3c] combines a 1,3-diketoenolate anion with an imidazolium cation. The system is isoconjugate to
an even non-alternant hydrocarbon dianion and is a conjugated mesomeric betaine (class 4).
Conclusions
Syntheses of tetraoxygenated terephthalates have been performed starting from the readily availalbe dichloroquinone esters 2 via
pyridine-induced SNAr reactions with oxygen nucleophiles. The intermediary mesomeric pyridinium quinolate betaines 4 (Liebermann
betaines) have been fully characterized by X-ray crystal structure analysis and NMR spectroscopy. The components 11 and 12 of the
dihydroxyquinone dicarboxylate/tetrahydroxyterphthalate redox-system have been synthesized via hydrolysis of dichloroquinone 2 or
betaine 4b and unequivocally characterized by spectral and X-ray crystallographic methods. An application of betaines 4 to serve as
ligand precursors for the synthesis of metal-organic coordination polymers in aqueous solution has been suggested.
Appendix
This paper is dedicated to the memory of Hans Liebermann and David Lisser, who first prepared and described betaine 4b. Hans
Liebermann (26.3.1876 – 11.9.1938) was a lecturer and professor of organic chemistry at Technische Hochschule Berlin, where he
established a research program on the synthesis of organic dyes using succinylosuccinates (cyclohexane-1,4-dione-2,5-dicarboxylates) as
versatile starting materials.[27] In 1934, he was removed from his position due to racial (antisemitic) and political reasons, which led to his
eventual suicide.[28] David Lisser (28.11.1906 – 15.8.1942) was born in Jaroslawl (Russia) into a (Jewish) family that was forced to emigrate
to Germany in 1920 for political reasons.[11] He studied chemistry at TH Berlin and worked towards a doctoral degree with H. Liebermann
in 1931/2. The synthesis of betaine 4b was described in his dissertation as part of work clarifying the role of pyridine in reactions of 2b
with nucleophiles.[11] He later moved to France, but was deported to the Auschwitz concentration camp during World War II, where he
died.[29]
Experimental Section
General
Reaction temperatures refer to oil-bath temperatures. Melting points were measured on a metal block with a mercury thermometer and
are not corrected.[30] TLC were performed on coated plates (F254 indicator) and detected by UV and phosphomolybdate stain.
Preparative chromatography (CC = column chromatography) was performed on silica gel 60 (0.040–0.063 mm) using pressured air (0.2
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bar) for flash elution. NMR spectra were recorded at room temperature (ca 24 °C). Proton chemical shifts are given relative to internal
tetramethylsilane in CDCl3 or referenced against residual solvent signal ([D5]-DMSO = δ 2.50, [D2]-MeCN = δ 1.94). 13C-NMR chemical
shifts are referenced relative to solvent signals (CDCl3 = δ 77.00; [D6]-DMSO = δ 39.52; [D3]-MeCN = δ 1.32). Unless otherwise mentioned,
chemicals were obtained from commercial suppliers and used as received. The starting chloroquinone esters 2 and terephthalate 7a were
obtained as earlier reported.[13]Succinylosuccinates 5a/b re commercially available. Solvents were used as received from suppliers.
Acetone used for the preparation of betaines must contain residual water as discussed in the text.
Abbreviations
aq = aqueous solution of; tBuOMe = tert-butyl-methyl ether; CC = column chromatography; DMAP = 4-(N,N’-dimethylamino)pyridine;
DMF = N,N-dimethylformamide; (1R)-menthyl-(oxy) = (1R,2S,5R)-(2-isopropyl-5-methyl)-cyclohexyl-(oxy)]; NBS = N-bromosuccinimide;
NCS = N-chlorosuccinimide; Py = pyridine; sat = saturated solution of.
Crystallography
CCDC 230927 (4f), 230928 (14), 1506150 (11) and 1506151 (12) contain supplementary crystallographic information for this work. These
data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. See the
Supporting Information for information on the structure solution.
Bromoquinones and derived compounds
Dimethyl 2,5-dibromo-3,6-dioxo-cyclohexa-1,4-diene-1,4-dicarboxylate (6a): Bromine (5.2 mL, 102 mmol, 10 equiv.) was added in
portions to a suspension of 7a (2.28 g, 10.0 mmol) in HOAc (40 mL) with stirring. A dark brown solution formed with warming. A few mL
of water were added, and the reaction mixture was stirred for 1 d at r.t. The resulting yellow suspension was filtered and the solid washed
with a little HOAc to give yellow crystals (3.15 g, 82%). M.p. 249–251 °C (lit. 250–251 °C).[31] IR (KBr): 2958w, 2847w, 1742s, 1676s, 1602m,
1437m, 1298s, 1235m, 1112s, 963m, 912m, 826m, 730w. 1H-NMR (395 MHz, CDCl3): 3.99 (s, 6 H, 2 OMe). 13C-NMR (99 MHz, CDCl3): 53.5
(CH3); 134.1 (C); 141.2 (C); 162.1 (C); 173.8 (C). Anal. calc. for C10H6Br2O6 (381.96): C 31.44, H 1.58; found C 31.31, H 1.49.
Diethyl 2,5-dibromo-3,6-dioxo-cyclohexa-1,4-diene-1,4-dicarboxylate (6b): While this compound is probably best synthesized by
reaction of either 5b or 7b with Br2,[14][15] a non-optimized procedure using NBS as brominating reagent is given here: To a suspension of
5b (5.685 g, 22.2 mmol) in HOAc (25 mL) at 80 °C, NBS (4.2 g, 23.6 mmol) was added in portions. After 1.5 h at 85 °C, additional NBS (12.5
g, 70.2 mmol) was added in portions, causing evolution of Br2-vapors. The reaction mixture was stirred for 6 h at 70 °C. During this time, a
suspension formed (presumably of the product), but later the material dissolved again (reduction to 8b). Another portion of NBS (5.0 g,
28.1 mmol) was added to the reaction solution, which turned to a suspension over 15 min. Heating was discontinued and the vessel set
aside for crystallization. Filtration and washing with HOAc (20 mL) and water (2 × 20 mL) gave yellow crystals (4.171 g, 46%) of 6b after
drying in high vacuum. M.p. 223–227 °C (lit. 227 °C).[27d] IR (KBr): 2991w, 2971w, 2944w, 2906w, 1733s, 1676s, 1605m, 1559w, 1472w,
1444w, 1364m, 1287s, 1243m, 1126s, 1106s, 1013m, 862m, 845m, 729w. 1H-NMR (395 MHz, CDCl3): 1.40 (t, 3J(H,H) = 7.1, 6 H, 2 CH3 of
OEt); 4.47 (q, 3J(H,H) = 7.1, 4 H, 2 OCH2). 13C-NMR (99 MHz, CDCl3): 13.7 (CH3); 63.3 (CH2); 137.6 (C); 140.3 (C); 160.7 (C); 174.3 (C). Anal. calc.
for C12H10Br2O6 (410.01): C 35.15, H 2.46; found C 35.31, H 2.44.
Dimethyl 2,5-dibromo-3,6-dihydroxy-terephthalate (8a): A suspension of 6a (1.776 g, 4.65 mmol) in CH2Cl2 (20 mL) and a solution of
Na2S2O4 (85%; 2.17 g, 9.3 mmol) in water (30 mL) were combined and vigorously stirred for 30 min at r.t. The CH2Cl2 was carefully
removed (foaming may occur!) in vacuum at a rotatory evaporator to give an aqueous suspension of colorless crystals. Filtration, washing
of the solid with water and drying in high vacuum gave white crystals of 8a (1.679 g, 94%). This colorless material dissolves with yellow-
green color in CH2Cl2 (solvatochromism). M.p. 204–206 °C (lit. 205 °C).[32] 1H-NMR (395 MHz, CDCl3): 4.04 (s, 6 H, 2 OMe); 8.88 (s, 2 H, 2
OH). 13C-NMR (99 MHz, CDCl3): 53.1 (CH3); 109.7 (C); 121.7 (C); 149.1 (C); 167.6 (C). IR (KBr): 3239m br., 1696s, 1438m, 1414m, 1319m,
1286m, 1209m, 972m, 821m. Anal. calc. for C10H8Br2O6 (383.98): C 31.28, H 2.10; found C 31.17, H 1.98.
Dimethyl 2,5-dibromo-3,6-dimethoxy-terephthalate: The dimethylether derivative of hydroquinone 8a was prepared for further
characterization: To a solution of 8a (775 mg, 2.02 mmol) in DMF (2 mL) and MeI (1.0 mL, 16 mmol), NaH (60% in oil; 170 mg, 4.25 mmol)
was added in portions. Gas evolved, and the reaction mixture turned into a thick slurry with warming. After dilution with DMF (2 mL) and
stirring for 1 h at 60 °C, the mixture was diluted with tBuOMe and quenched with water. The organic phase was washed with sat aq NaCl
(2 ×) and evaporated to dryness. CC (tBuOMe/hexanes 1:5) resulted in incomplete separation, thus all fractions containing product were
combined and evaporated to dryness. The crude product was dissolved in CH2Cl2 and MeOH. CH2Cl2 was slowly evaporated in vacuum
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using a rotatory evaporator. The resulting crystal suspension was filtered and the solid washed with MeOH to give colorless, sugar-like
crystals (771 mg, 93%). M.p. 162.5–164.5 °C. IR (KBr): 2946m, 2859w, 1731s, 1458m, 1440m, 1377s, 1262s, 1138m, 1014s, 961m, 808w. 1H-
NMR (395 MHz, CDCl3): 3.88 (s, 6 H, 2 OMe); 3.99 (s, 6 H, 2 OMe). 13C-NMR (99 MHz, CDCl3): 53.0 (CH3); 62.6 (CH3); 114.1 (C); 134.3 (C);
151.5 (C); 165.3 (C).
Diethyl 2,5-dibromo-3,6-dihydroxy-terephthalate (8b): To a suspension of 6b (315.5 mg, 0.77 mmol) in HOAc (0.5 mL) at 85 °C,
HBr·HOAc (0.57 mL, 3.2 mmol) was added dropwise with stirring. The bromine vapors that developed were occasionally removed by an
air-stream. After 15 min, the reaction mixture was diluted with more HOAc (1 mL). Stirring was continued for 1 h at 85 °C. The reaction
mixture was cooled and diluted with tBuOMe. The reaction solution was washed with water (2 ×), sat aq NaHCO3 (1 ×) and water (2 ×).
The organic phase was dried (Na2SO4), filtered, and evaporated to give a crude product, which was recrystallized by dissolving in
CH2Cl2/hexane and slowly evaporating to ca. 2 mL volume. Filtration and washing of the solid with a little hexane gave colorless needles
(231.6 mg, 73%). M.p. 156–157 °C (lit. 156 °C,[33] 157 °C[34]). IR (KBr): 3221s br., 2993w, 1694s br., 1473m, 1425s, 1370m, 1316s, 1299s, 1284s,
1205s, 1151m, 1098m, 1011m, 862m, 842m. 1H-NMR (395 MHz, CDCl3): 1.45 (t, 3J(H,H) = 7.1, 6 H, 2 CH3); 4.51 (q, 3J(H,H) = 7.1, 4 H, 2 OCH2);
8.94 (s, 2 H, 2 OH). 13C-NMR (99 MHz, CDCl3): 14.0 (CH3); 63.1 (CH2); 109.6 (C); 121.5 (C); 148.7 (C); 166.7 (C). Anal. calc. for C12H12Br2O6
(412.03): C 34.98, H 2.94; found C 34.89, H 2.85.
Synthesis of Liebermann’s betaines
2,5-Bis(ethoxycarbonyl)-3,6-dioxo-4-(1-pyridinium-1-yl)cyclohexa-1,4-dienolate (4b): Small scale reaction: A suspension of 2b (1.312 g,
4.085 mmol) in technical grade acetone (50 mL)a) was heated to 45–50 °C to effect complete dissolution. While the solution was still warm,
a solution of pyridine (1.32 mL, 16.35 mmol) in acetone (5 mL) was added dropwise over 10 min at r.t., causing a color change to red-violet.
Stirring was discontinued and the reaction flask kept at 4 °C overnight. The product crystallized in dark red-violet crystals, which were
isolated by filtration and washed with acetone. In the dry state, the color of the product is brown-red. The crude product (1.12 g, 79%) still
contained chlorideb) and was purified as follows: The solid was finely suspended in iPrOH (5 mL), lumps being broken up with a spatula
and using ultrasonication. The suspension was filtered and the product washed with iPrOH and Et2O. Drying in high vacuum gave a fine
red-brown powder (880 mg, 62%) containing only traces of chloride. Larger scale reaction with alternative purification: The reaction was
performed as above on a 26 mmol scale in technical grade acetone (320 mL).a) The crude product was suspended in acetone (20 mL) at
0 °C and abs. EtOH (20 mL) was added. The suspension was stirred for 15 min at 0 °C, and the product isolated by suction filtration and
washing with acetone. The yield was 59%, and the product entirely free of chloride.b) Recrystallization of the material is possible by
preparing filtered, warm (50 °C) solutions of the material in acetonitrile and cooling them to 0 °C (or –20 °C) for several hours. Notes: a)
For the reaction to proceed it is necessary that the acetone contains traces of water, which is often the case if “aged” solvent is used, but
may not be the case with a freshly opened bottle. To ensure that the reaction takes place, a few equivalents of water (relative to starting
material) may be added to the solvent at the outset of the reaction. b) The presence of chloride was tested as follows: a sample of the
product was dissolved in a little deionized water with addition of a few drops of dilute 10% aqueous HNO3. Upon addition of aqueous
AgNO3, generation of a turbidity or precipitation of AgCl indicated the presence of chloride. M.p. >171 °C dec. (lit. 194 °C, dec.).[6] IR (KBr):
3121w, 3090w, 3061w, 2996w, 1740s, 1718s, 1676s, 1624s, 1577s, 1555s, 1473m, 1400m, 1375m, 1314m, 1282m, 1234m, 1193m, 1060w,
1019w, 783w, 745w, 677w. 1H-NMR (395 MHz, [D3]-MeCN): 1.00 (t, 3J(H,H) = 7.1, 3 H, CH3 of Et); 1.22 (t, 3J(H,H) = 7.1, 3 H, CH3 of Et); 4.10 (q,
3J(H,H) = 7.1, 2 H, OCH2); 4.14 (q, 3J(H,H) = 7.1, 2 H, OCH2); 8.14–8.19 (m, 2 H-Py); 8.66–8.70 (m, 2 H-Py); 8.71 (tt, 3J(H,H) = 7.9, 4J(H,H) = 1.4,
1 H-Py). 1H-NMR (395 MHz, [D6]-DMSO): 0.93 (t, 3J(H,H) = 7.1, 3 H, CH3 of Et); 1.17 (t, 3J(H,H) = 7.0, 3 H, CH3 of Et); 4.07 (ψ-quint, 3J(H,H) =
7.1, 4 H, 2 OCH2); 8.30–8.36 (m, 2 H-Py); 8.84 (tt, 3J(H,H) = 7.9, 4J(H,H) = 1.3, 1 H-Py); 9.15–9.21 (m, 2 H-Py). 13C-NMR (99 MHz, [D6]-
DMSO): 13.4 (CH3); 14.2 (CH3); 59.3 (CH2); 62.7 (CH2); 109.7 (C); 127.9 (CH); 130.0 (C); 145.8 (C); 146.1 (CH); 149.1 (CH); 161.0 (C); 167.0 (C);
169.4 (C); 170.1 (C); 181.8 (C). Anal. calc. for C17H17NO7 (345.30): C 59.13, H 4.38, N 4.06; found C 59.37, H 4.54, N 3.90.
2,5-Bis(benzyloxycarbonyl)-3,6-dioxo-4-(1-pyridinium-1-yl)cyclohexa-1,4-dienolate (4c): To a solution of 2c[13] (455 mg, 1.02 mmol) in
acetone (10 mL) and CH2Cl2 (10 mL), a solution of pyridine (0.42 mL, 5.2 mmol) in acetone (5 mL) was added dropwise. A reddish-brown
suspension resulted, which was stirred for 1 h at r.t. Solvents were removed in vacuo and the residue stirred with MeOH (10 mL) for 5 min.
Filtration and washing of the solid with a little MeOH and tBuOMe gave brown powder (255 mg, 53%). The material is soluble in DMSO,
not very soluble in MeCN or MeOH. Note: The yield is low due to losses into the mother liquor. Less MeOH might be used for the pre-
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filtration step. M.p. 152–157 °C dec. IR (KBr): 3063w, 3029w, 1740m, 1696s br., 1623m, 1565s br., 1473m, 1548w, 1399m, 1363m, 1297s,
1175m br., 1064w, 736w, 696w. 1H-NMR (395 MHz, [D6]-DMSO): 5.10 (s, 2 H, OCH2); 5.12 (s, 2 H, OCH2); 7.10–7.18 (m, 2 H-Ph); 7.23–7.47
(m, 8 H-Ph); 8.14 (br. t, 3J(H,H) ≈ 7, 2 H-Py); 8.68 (t × m, 3J(H,H) ≈ 7.9, 1 H-Py); 9.10 (br. d, 3J(H,H) = 6.4, 2 H-Py). 13C-NMR (99 MHz, [D6]-
DMSO): 64.8 (CH2); 67.9 (CH2); 108.6 (C); 127.7 (CH); 128.0 (CH); 128.1 (CH); 128.8 (CH); 129.1 (CH); 129.1 (CH); 129.2 (CH); 129.8 (C); 135.0
(C); 137.7 (C); 145.8 (CH); 145.9 (C); 148.8 (CH); 160.9 (C); 166.6 (C); 169.9 (C); 170.3 (C); 181.6 (C). Anal. calc. for C27H19NO7 (469.44): C
69.08, H 4.08, N 2.98; found C 68.79, H 4.12, N 2.72.
2,5-Bis(((1R)-menthyloxy)carbonyl)-3,6-dioxo-4-(1-pyridinium-1-yl)cyclohexa-1,4-dienolate (4d): A solution of pyridine (202 μL, 2.50
mmol) in acetone (5 mL) was added dropwise to a solution of 2d[13] (273.8 mg, 0.506 mmol) in acetone (4 mL). The resulting deep-violet
solution was kept 1 h at r.t., then stored overnight at –20 °C for crystallization. The solid was isolated by filtration and re-dissolved in
MeCN (10 mL) and acetone (20 mL). Silver oxide (200 mg, 0.86 mmol) was added and the suspension vigorously stirred for 30 min at r.t.
Filtration through Celite (washing with acetone) gave a deep-violet solution, which was evaporated to dryness. The resulting dark solid
was dissolved in MeCN (2 mL) and CH2Cl2 (10 mL). The solution was filtered, evaporated to a small volume (ca. 3 mL), and overlayered
with Et2O (4 mL). Crystallization by standing at 0 °C for several hours gave dark crystals which were washed with Et2O (217 mg, 76%). The
material is insoluble in water, soluble in MeOH (red color). Water precipitates the product from a MeOH-solution. A silver test (see above;
in MeOH/H2O solution) was negative. M.p. 185–189 °C dec. IR (KBr): 2956m, 2871w, 1734m, 1696m, 1624w, 1561s br., 1472m, 1303m,
1195m, 962w. 1H-NMR (395 MHz, CDCl3): 0.58 (d, 3J(H,H) = 6.9, 3 H); 0.67–1.02 (m, 5 H); 0.76 (d, 3J(H,H) = 6.9, 3 H); 0.78 (d, 3J(H,H) = 7.0, 3
H); 0.83 (d, 3J(H,H) = 6.6, 3 H); 0.87 (br. d, 3J(H,H) = 6.7, 6 H); 1.02–1.14 (m, 2 H); 1.19–1.29 (m, 1 H); 1.29–1.73 (m, 8 H); 2.07–2.16 (m, 1 H);
2.28 (sept × d, 3J(H,H) = 6.9, 2.6, 1 H); 4.66 (td, 3J(H,H) = 10.9, 4.3, 1 H); 4.85 (td, 3J(H,H) = 10.9, 4.3, 1 H); 8.22 (ψ-t, 3J(H,H) ≈ 7.4, 2 H); 8.71
(tt, 3J(H,H) = 7.9, 4J(H,H) = 1.3, 1 H); 8.75 (br. s, 2 H). 13C-NMR (99 MHz, CDCl3): 15.4 (CH3); 15.7 (CH3); 20.4 (CH3); 20.7 (CH3); 21.5 (CH3); 21.8
(CH3); 22.5 (CH2); 22.7 (CH2); 25.0 (CH); 25.5 (CH); 31.0 (CH); 31.3 (CH); 33.5 (CH2); 34.1 (CH2); 40.1 (CH2); 40.9 (CH2); 46.5 (CH); 46.8 (CH);
74.1 (CH); 78.2 (CH); 110.4 (C); 127.6 (br., CH); 131.3 (C); 144.3 (C); 145.5 (CH); 148.1 (CH); 160.7 (C); 166.6 (C); 169.0 (C); 169.7 (C); 180.5 (C).
Anal. calc. for C33H43NO7 (565.70): C 70.06, H 7.66, N 2.48; found C 69.76, H 7.46, N 2.37; sample recryst. from MeCN–tBuOMe: found C
69.88, H 7.69, N 2.32.
4-(3,5-Dimethyl-1-pyridinium-1-yl)-2,5-bis(ethoxycarbonyl)-3,6-dioxocyclohexa-1,4-dienolate (4e): Quinone 2b (963 mg, 3.0 mmol)
was dissolved in warm acetone (30 mL) and the solution cooled to r.t. A solution of 3,5-dimethylpyridine (1.37 mL, 12.0 mmol) in acetone
(10 mL) was added with gentle stirring. The resulting deep-violet reaction mixture was stored at 0 °C overnight to yield mixed dark violet
and colorless crystals. The solids were isolated by filtration and washed with some acetone. The material was finely divided in absolute
EtOH (10 mL) at 0 °C and stirred for 5 min. Filtration and washing of the solids with cooled EtOH (3 mL) and drying gave brown-red
powder (737.7 mg, 66%). The EtOH-wash is accompanied by losses, but removes chloride salts (negative Ag+-test, see above). M.p. 186 °C
dec. IR (KBr): 3042m, 2978w, 1727m, 1696s br., 1618m, 1566s br., 1477m, 1402m, 1368m, 1319m, 1290m, 1198m, 1096w, 1036w. 1H-NMR
(395 MHz, [D3]-MeCN): 1.02 (t, 3J(H,H) = 7.1, 3 H, CH3 of OEt); 1.21 (t, 3J(H,H) = 7.1, 3 H, CH3 of OEt); 2.52 (q, 4J(H,H) = 0.6, 6 H, 2 Me-Py);
4.12 (q, 3J(H,H) = 7.1, 2 H, OCH2); 4.13 (q, 3J(H,H) = 7.1, 2 H, OCH2); 8.34–8.36 (m, 1 H-Py); 8.36–8.38 (m, 2 H-Py). 13C-NMR (99 MHz, [D3]-
MeCN): 14.2 (CH3), 14.9 (CH3); 18.6 (CH3); 60.8 (CH2); 64.0 (CH2); 111.3 (C); 132.1 (C); 140.1 (C); 143.3 (br., CH); 146.6 (C); 151.2 (CH); 162.2
(C); 168.5 (C); 170.9 (C); 171.2 (C); 183.2 (C). Anal. calc. for C19H19NO7 (373.36): C 61.12, H 5.13, N 3.75; found C 60.98, H 4.99, 3.56.
2,5-Bis-ethoxycarbonyl-3,6-dioxo-4-((4-dimethylamino)-1-pyridinium-1-yl)-cyclohexa-1,4-dienolate (4f): To a solution of 2b (172 mg,
0.536 mmol) in acetone (15 mL; with 1 drop of water), a solution of DMAP (230 mg, 1.88 mmol) in acetone (10 mL) was added quickly (an
orange precipitate forms initially) and the reaction mixture stirred 1 h at r.t. The resulting precipitate was isolated by filtration and
washed with a little acetone to remove strongly coloring matters. The solid was redissolved in MeCN (5 mL) and acetone (10 mL). Silver
oxide (120 mg, 0.5 mmol) was added and the suspension vigorously stirred for 5 minutes. Filtration through Celite and evaporation of the
filtrate gave a crude solid, which was recrystallized from MeCN (2 mL) and Et2O (6 mL; overlayering) at 0 °C. Filtration and washing of the
solid with a little Et2O gave dark brown-violet solid (159.2 mg, 76%). The material is soluble in CH2Cl2 and acetone with dark-violet color,
or in water with brown-red color. Crystals suitable for X-ray diffraction were obtained from dark-violet solutions of 4f in CH2Cl2–hexane.
M.p. 187–189 °C dec. IR (KBr): 2982w, 1738w, 1684m, 1659s, 1558s, 1309m, 1229m, 1194m. 1H-NMR (395 MHz, [D3]-MeCN): 1.13 (t, 3J(H,H)
= 7.1, 3 H, CH3 of OEt); 1.23 (t, 3J(H,H) = 7.1, 3 H, CH3 of OEt); 3.23 (s, 6 H, NMe2); 4.14 (q, 3J(H,H) = 7.1, 2 H, OCH2); 4.18 (q, 3J(H,H) = 7.1, 2 H,
OCH2); 6.91 (A of AB, ψ-d, 3J(H,H) = 8.0, 2 H-Py); 7.85 (B of AB, ψ-d, 3J(H,H) = 8.0, 2 H-Py). 13C-NMR (99 MHz, [D3]-MeCN): 14.4 (CH3); 14.9
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(CH3); 41.3 (CH3); 60.7 (CH2); 63.8 (CH2); 108.2 (CH); 111.4 (C); 132.5 (C); 143.3 (CH); 145.8 (C); 158.7 (C); 163.6 (C); 169.0 (C); 170.8 (C); 172.6
(C); 184.1 (C). Anal. calc. for C19H20N2O7 (388.37): C 58.76, H 5.19, N 7.21; found C 58.48, 5.05, 7.26.
Reaction of Liebermann’s betaines with oxygen nucleophiles
Diethyl 2,5-dihydroxy-3,6-dioxo-cyclohexa-1,4-diene-1,4-dicarboxylate (11):[16] Chloroquinone 2b (322 mg, 1 mmol) was added with
stirring to a solution of NaOH (880 mg, ca. 20 mmol) in H2O (50 mL) to give a homogeneous, dark-yellow solution. After stirring for 1 h at
r.t., the solution was quickly neutralized and slightly acidified (pH 3) with aq 2.4 M HCl, followed by evaporation to dryness. The residue
was dissolved in hot EtOH (20 mL) and CH2Cl2 (20 mL). After standing at 4 °C, the mixture was filtered over Celite and the filtrate
evaporated to dryness. The solid residue was dissolved in CH2Cl2 (10 mL), the solution filtered over Celite (removes huminous material)
and evaporated to a volume of ca 3 mL. On overlayering with hexane (5 mL) and standing overnight at 4°C, yellow needles separated
(228 mg, 80%). Crystals for X-ray were obtained by placing a vial with a CHCl3 solution of the substance into a diffusion chamber filled
with heptane. M.p. 153–154.5 °C (lit. 152 °C).[16a] IR (KBr): 3440m br., 3006m, 1681s, 1637s, 1566s, 1479m, 1409m, 1380m, 1322s, 1210s,
1025m, 921m. 1H-NMR (300 MHz, CDCl3): 1.44 (t, 3J(H,H) = 7.1, 6 H, 2 CH3 of OEt); 4.48 (q, 3J(H,H) = 7.1, 4 H, 2 OCH2); 13.73 (br. s, 2 OH,
92.5% abundance); 15.00 (br s, 2 OH, 7.5% abundance). 1H-NMR (400 MHz, (D6)-DMSO): 1.23 (t, 3J(H,H) = 7.1, 6 H, 2 CH3 of OEt); 4.20 (q,
3J(H,H) = 7.1, 4 H, 2 OCH2); 9.53 (br s, 2 OH). 13C-NMR (75.5 MHz, CDCl3): 14.0 (CH3); 63.4 (CH2); 106.6 (C); 169.5 (C); 1 signal not visible due
to broadening by dynamic exchange. 13C-NMR (101 MHz, (D6)-DMSO): 14.10 (C); 60.62 (C); 110.23 (C); 163.31 (C); 168.51 (C). ESI-MS (neg.
mode): 283 ([M–H]–), fragmentation pathway 237, 209, 137, 92. Anal. calc. for C12H12O8 (284.22): C 50.71, H 4.26; found C 50.29, H 4.20.
Diethyl 2,3,5,6-tetrahydroxyterephthalate (12): To a suspension of chloroquinone 2b (698.4 mg, 2.175 mmol) in H2O (50 mL), aq 1 M
NaOH (20 mL, 20 mmol) was added in portions of 5 mL. After stirring for 1 h at r.t., the resulting, homogeneous, dark-yellow-brown
solution was treated with a solution of Na2S2O4 (85%; 1.73 g, 8.5 mmol) in water (10 mL). After stirring for 10 min at r.t., the solution was
neutralized and slightly acidified with dilute aq 2 M HCl (ca 15 mL), inducing precipitation. The suspension was stirred in an ice bath for 30
min and the product isolated by filtration and washing with ice water, followed by a mixture of ice-water/acetone. The resulting gold-
yellow needles were dissolved in sufficient CH2Cl2 and the solution filtered. The filtrate was evaporated to a small volume (3–4 mL), over-
layered with pentane (ca 10 mL) and set aside for crystallization. After 1 d, the mother liquors were removed with a pipette and the
crystalline solid was washed 3 times with pentane, each time removing the washing phases with a pipette. After drying in vacuum,
yellow-orange crystals remained (527.3 mg, 85%), which were moderately soluble in CH2Cl2, CDCl3 or EtOAc, but well soluble in DMSO. A
crystal for X-ray structural analysis was obtained by slow evaporation of a CDCl3 solution from an NMR tube (Figure S-1). M.p. 181–182 °C
dec. (lit. 178 °C).[6][17] 1H-NMR (400 MHz, CDCl3): 1.51 (t, 3J(H,H) = 7.1, 6 H, 2 CH3 of OEt); 4.61 (q, 3J(H,H) = 7.1, 4 H, 2 OCH2); 9.03 (s, 4 H, 2
OH). 1H-NMR (400 MHz, [D6]-DMSO): 1.29 (t, 3J(H,H) = 7.1, 6 H, 2 CH3 of OEt); 4.31 (q, 3J(H,H) = 7.1, 4 H, 2 OCH2); 8.82 (br s, 4 H, 4 OH).
13C-NMR (101 MHz, CDCl3; ref. = 77.16 ppm): 14.30 (CH3); 63.58 (CH2); 105.50 (C); 139.92 (C); 169.23 (C). 13C-NMR (101 MHz, [D6]-DMSO):
14.02 (CH3); 61.20 (CH2); 112.06 (C); 136.67 (C); 166.97 (C).
Zinc(II) salt of 11 (13): To a dark-red solution of betain 4b (207.6 mg, 0.784 mmol) in water (15 mL), ZnCl2 (570 mg, 4.18 mmol) was added
and the mixture stirred at r.t. A turbid yellow-red suspension (yellow precipitate, red solution) was quickly formed. After stirring overnight,
the suspension was filtered and the solids washed with water. The solid was dried in high vacuum and placed in an oven at 100 °C for 2 h
to give yellow-brown, fine powder (285.7 mg, 95%) analyzing approximately as [Zn(C12H10O8)(H2O)2]. Anal. calc. for C12H14O10Zn (383.61):
C 37.57, H 3.68, Zn 17.04, found C 37.89, 38.04, H 4.11, 3.91, Zn 16.8 (EDTA titration); calc. for Zn(C12H10O8)(H2O)1.8: C 37.93, H 3.61, Zn
17.21.
Dimethyl 5-hydroxy-2-(3,4-methylenedioxyphenyloxy)-3,6-dioxo-cyclohexa-1,4-diene-1,4-dicarboxylate, pyridinium salt (14): To a
suspension of 6a (310 mg, 0.812 mmol) in acetone (10 mL) and 5 drops of water, a solution of pyridine (0.38 mL, 4.7 mmol) in acetone (6
mL) was added dropwise. After standing for 1 h at r.t., a solution of sesamol (benzo[d][1,3]dioxol-5-ol; 330 mg, 2.39 mmol) in acetone (6
mL) was added to the violet suspension, and the reaction mixture stirred for 20 h at r.t. The resulting orange suspension was filtered and
the solids washed with a little acetone. After drying in high vacuum, 302 mg of a brown powder remained. A batch of the crude product
(177 mg) was stirred with warm MeCN (5 mL), filtered, and set aside in a closed vessel at 4 °C. After 1 week, a mixture of red-brown and
yellow crystals was isolated by decantation and washed with a little MeCN/tBuOMe. Another recrystallization of this material from
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MeCN/tBuOMe again provided a mixture of two kinds of crystals (yellow and red-brown). A few of the red-brown crystals of 14 were
separated manually and submitted to X-ray diffraction structure determination. 1H-NMR (395 MHz, CDCl3): 3.70 (s, 3 H, OMe); 3.87 (s, 3 H,
OMe); 5.98 (s, 2 H, OCH2O); 6.49 (dd, 3J(H,H) = 8.4, 4J(H,H) = 2.5, 1 H-Ar); 6.64 (d, 4J(H,H) = 2.5, 1 H-Ar); 6.70 (d, 3J(H,H) = 8.4, 1 H-Ar);
7.68–7.73 (m, 2 H-Py); 8.15 (tt, 3J(H,H) = 7.9, 4J(H,H) = 1.7, 1 H-Py); 8.81–8.84 (m, 2 H-Py); 12.99 (br s, 1 N+H). 13C-NMR (99 MHz, CDCl3):
52.2 (CH3); 52.5 (CH3); 101.6 (CH); 101.8 (CH2); 108.0 (CH); 111.1 (CH); 121.7 (C); 125.7 (CH); 127.7 (C); 141.5 (CH); 145.0 (C); 145.8 (CH);
148.5 (C); 148.8 (C); 151.0 (C); 155.6 (C); 162.9 (C); 168.0 (C); 169.0 (C); 175.8 (C).
Supplementary Material
Supporting information (figures, 1H and 13C NMR spectra) for this article is available on the WWW under http://dx.doi.org/10.1002/MS-
number.
Acknowledgements
The authors thank Ms. Sachiyo Kubo for the data collection of 14, Prof. Dr. Yuji Ohashi (TIT) for kindly providing access to the CCD
diffractometer and supercomputer facility, Dr. Alexander Pöthig (TUM) for crystallographic advice (11, 12) and Prof. Dr. Andreas Schmidt
(Clausthal University of Technology) for comments on betaine classification. Part of the project was supported by a fellowship from the
Japan Society for the Promotion of Science (JSPS) to LH.
Author Contribution Statement
Project design by LH and KS. Experiments, data analysis and writing of the manuscript by LH, with contributions to data analysis and
writing by PN. X-ray crystallography by PA and PN.
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