Generation of trityl radicals by nucleophilic quenching of tris(2,3,5,6-tetrathiaaryl)methyl cations and practical and convenient large-scale synthesis of persistent tris(4-carboxy-2,3,5,6-tetrathiaaryl)methyl radical

Article abstract of DOI:10.1002/ejoc.201300176

Tris(2,3,5,6-tetrathiaaryl)methyl cations, which were generated from the corresponding triarylmethanols in the presence of strong acids, underwent reaction with nucleophiles to give trityl radicals, as the product of a one-electron reduction of the carbocation. Depending on the nature of the nucleophile, the only byproducts were either diamagnetic quinone methides or asymmetrical monosubstituted trityl radicals. Herein, we report a protocol for the large-scale synthesis of the Finland trityl, which has the advantage of high overall yield and reproducibility. Tris(2,3,5,6-tetrathiaaryl)methyl cations, which were generated from the corresponding triarylmethanols and strong acids, underwent reaction with nucleophiles to give trityl radicals. Depending on the nucleophile, the only byproducts were diamagnetic quinone methides or asymmetrical monosubstituted trityl radicals. A protocol for the large-scale synthesis of the Finland trityl is reported. Copyright

Full text of DOI:10.1002/ejoc.201300176

FULL PAPER
DOI: 10.1002/ejoc.201300176
Generation of Trityl Radicals by Nucleophilic Quenching of Tris(2,3,5,6-
tetrathiaaryl)methyl Cations and Practical and Convenient Large-Scale
Synthesis of Persistent Tris(4-carboxy-2,3,5,6-tetrathiaaryl)methyl Radical
Olga Yu. Rogozhnikova,[a] Vladimir G. Vasiliev,[a] Tatiana I. Troitskaya,[a]
Dmitry V. Trukhin,[a] Tatiana V. Mikhalina,[a] Howard J. Halpern,[b] and
Victor M. Tormyshev*[a,c]
Keywords: Radicals / Carbocations / Quinones / Reaction mechanisms / Synthesis design
Tris(2,3,5,6-tetrathiaaryl)methyl cations, which were gener- the only byproducts were either diamagnetic quinone
ated from the corresponding triarylmethanols in the presence
of strong acids, underwent reaction with nucleophiles to give
trityl radicals, as the product of a one-electron reduction of
the carbocation. Depending on the nature of the nucleophile,
methides or asymmetrical monosubstituted trityl radicals.
Herein, we report a protocol for the large-scale synthesis of
the Finland trityl, which has the advantage of high overall
yield and reproducibility.
Introduction
The family of tris(2,3,5,6-tetrathiaaryl)methyl radicals
(trityls, TAMs), which was first designed by Nycomed In-
novations[1] (see Figure 1), has recently been used for a
number of magnetic resonance applications because of their
favorable relaxation and spectral properties. These trityl
compounds demonstrate high chemical stability and excel-
lent solubility in aqueous solutions, which make them at-
tractive spin probes in numerous applications of low-fre-
quency electron paramagnetic resonance (EPR) for in vivo
detection of free radicals,[2] 3D EPR imaging,[3] and other
studies such as for the simultaneous measurement of redox
status and oxygen concentration using dual function ni-
troxide-trityl biradicals,[4] intracellular oxymetry,[5] the
measurement of concentration of a superoxide anion[6] and
pH in a biologically relevant range of acidity,[7] and studies
of molecular diffusion in microheterogeneous systems.[8]
Trityl radicals also have a single, narrow electron paramag-
netic resonance line, even at high fields, and have long relax-
ation times in liquid solutions, which make them useful
electron spin reagents for studies of dynamic nuclear polar-
ization.[9]
Figure 1. Molecular structures of representative TAMs.
The strong interest in trityls has stimulated numerous ef-
forts towards optimization of synthetic strategies and
searches for efficient approaches to a large-scale synthesis
of these challenging compounds. The major part of these
studies has focused on the simplest representative in the
series of highly persistent trityls Ϫ tris(8-carboxy-2,2,6,6-
tetramethylbenzo[1,2-d;4,5-dЈ]bis[1,3]dithiol-4-yl)methyl (alias
Finland trityl, see Figure 1). Although the preparation of
the Finland trityl has been reported both in patent and aca-
demic literature,[10–12] we have found that these synthetic
procedures allow sufficient room for further improvement.
Herein, we describe a practical procedure for the large-scale
synthesis of the Finland trityl radical. The unexpected effect
[a] Vorozhtsov Novosibirsk Institute of Organic Chemistry,
9 Acad. M.A. Lavrentjev Ave., Novosibirsk 630090, Russia
Fax: +7-383-330-97-52
E-mail: torm@nioch.nsc.ru
Homepage: http://www.nioch.nsc.ru/eng/labs/mcg_e.htm
[b] The Center for EPR Imaging in vivo Physiology, Department
of Radiation and Cellular Oncology, the University of Chicago,
Chicago, IL 60637, USA
[c] Department of Natural Sciences, Novosibirsk State University,
2 Pirogov St., Novosibirsk 630090, Russia
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300176.
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of the formation of TAMs as a result of the nucleophilic not require lengthy and tedious column chromatography.
quenching of tris(2,3,5,6-tetrathiaaryl)methyl cations is also Instead, we used the simple and fast procedure of heating
reported.
the crude material at reflux with 1:1 mixture of hexane and
carbon tetrachloride, which readily afforded the highly pure
product 3 in a good yield of 66–72% based on arene 2 (56–
69%[10,11]).
Results and Discussion
Potentially, converting triarylmethanol 3 into the triple
ester 4 may be performed by lithiation of 3 with an excess
amount of nBuLi-TMEDA complex in benzene solution
followed by pouring the intermediate tris(lithium) derivative
into a large excess amount of diethyl carbonate.[1a,10] Unfor-
tunately, the direct application of the literature procedure
did not provide satisfactory results, and the yield of 4 never
reached 12%. Our attempt to improve the result by replac-
ing diethyl carbonate with sterically hindered di-tert-butyl
dicarbonate (DIBOC), which was recommended in the lit-
erature,[11] did not provide any notable effect.
The general concept for the synthesis of the Finland tri-
tyl was similar to that described in the literature,[1a,8,10–12]
but improvements were implemented at each step (see
Scheme 1). Tetra-tert-butylthiobenzene (1) was obtained by
analogy to a literature protocol[10] through the treatment of
tetrachlorobenzene with sodium tert-butylthiolate in anhy-
drous N,N-dimethylformamide (DMF) followed by heating
the reaction mixture at reflux for 4 h and stirring at ambient
temperature overnight. The reaction time was increased in
comparison to the prototype, which resulted in a slight in-
crease of the product yield (69–71% vs. 63%).
Initially, a somewhat respectable yield was only obtained
when benzene was replaced with hexane.[8] Under these
modified conditions, ester 4 was isolated in 16–36% yield
(44–45%[10,11]) after a lengthy and solvent-consuming chro-
matographic purification (see Exp. Section, Method A). A
possible rationale for the observed improvement is that hex-
ane is a very weak C–H acid, contrary to benzene, and,
therefore, this solvent is inert towards the nBuLi-TMEDA
complex and does not compete with 3 in the conversion to
an aryllithium derivative.[13]
Compound 1 was further converted into intermediate
thioacetonide 2 by heating at reflux with acetone. Boron
trifluoride and chloroform were used as the catalyst and
solvent, respectively, instead of HBF4 and toluene, which
was recommended by the literature sources. After the crude
material was heated at reflux with methanol, the product
was isolated in high yield (86–93% vs. 51–61%[10,11]). The
revised procedure was simple and high yielding and was
especially relevant to synthesis of the deuterated form of 2
(and all the further products) if [D6]acetone was used as the
ketone component.
Trityl
5 was generated by following an earlier
Triarylmethyl alcohol 3 was prepared by treatment of ar- method,[8,10] that is, the treatment of alcohol 4 with tri-
ene 2 with nBuLi and the subsequent addition of 0.32 equiv. fluoromethanesulfonic acid in dichloromethane (DCM) fol-
of diethyl carbonate. Purification of the crude product did lowed by reduction of the obtained cation with 1 equiv. of
Scheme 1. Reagents and conditions: (a) acetone (10 equiv.), BF3·Et2O solution (3 equiv.), d-10-camphorsulfonic acid (0.2 equiv.) in CHCl3,
93%; (b) nBuLi (2.5 m in hexane, 1.1 equiv.), ether as a solvent, diethyl carbonate (0.32 equiv.), 72%; (c) nBuLi (2.5 m in hexane, 10 equiv.),
hexane/N,N,NЈ,NЈ-tetramethyl-1,2-ethylenediamine (TMEDA) solution, diethyl carbonate (40 equiv.), 32%; (d) CF3SO3H (15 equiv.) in
dichloromethane, SnCl2 (1 equiv.), hydrolysis with aqueous KOH (10 equiv.), aqueous HCl, 92%; (e) nBuLi (2.5 m in hexane, 10 equiv.),
hexane/TMEDA solution, solid CO2, 62%; (f) Thionyl chloride (30 equiv.) in CHCl3/NEt3, ethanol in presence of pyridine, 98%; (g) tri-
fluoroacetic acid (TFA), SnCl2 (0.5 equiv.), 96%.
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Generation of Trityl Radicals by Nucleophilic Quenching of Cations
SnCl2. Hydrolysis of ester functions of the intermediate tri- strictly consistent with the original protocols, whereas
tyl radical with aqueous KOH and addition of aqueous others involved modifications of the reaction conditions, for
HCl converted the tris(carboxylate) into the acidic form of example, the presence or absence of atmospheric oxygen in
the Finland trityl. The latter was isolated in 92% yield the reaction vessel and the variation of the reaction time in
based on initial trityl alcohol 4 (see Exp. Section, Method the range of 6–36 h. Regardless of reaction conditions, the
C).
crude product was never a single component, but instead
On the basis of trityl alcohol 3, the overall yield of Fin- was two major components easily observable on TLC plates
land trityl (5) was low (15–33%). In addition, the synthesis (see Supporting Information). The products were identified
of tris(ester) 4 showed low reproducibility and required la- as trityl radical 5 and diamagnetic quinone methide 7 (see
borious chromatographic purification. These factors sub- Scheme 2), which were isolated in 52–56% and 13–19%
stantially limit the utility of any reaction pathway that relies yield, respectively (see Exp. Section).
on the participation of intermediates such as 4, especially
in the case of the large-scale production and synthesis of
the extra narrow-line form of the Finland trityl Ϫ the deu-
terated analogue of 5.
This explains our search for alternative methods for the
carboxylation of triarylmethanol 3. First, we turned to the
direct insertion of carboxy functions into the para positions
of the aryl moieties of the substrate. We found that a slurry
of the tris(lithium) derivative, which was obtained by treat-
ing 3 with nBuLi in TMEDA/hexane solution, readily
underwent reaction with solid carbon dioxide to afford tri-
acid 6 in a good isolated yield (52–62%). Purification of the
triacid was easy and fast, that is, the addition of brine to a
homogeneous aqueous solution of the sodium salt of crude
6 led to the immediate precipitation of the contaminants as
insoluble salts (i.e., the dicarboxylic and monocarboxylic
acids). Filtration of this mixture followed by addition of
aqueous HCl to the filtrate resulted in pure 6. This present
procedure not only is higher yielding than the reported
methods but also avoids the use of purification by column
chromatography.
Scheme 2. Synthesis of trityl 5 and quinoide 7 by treatment of tri-
arylmethanol 6 with TFA followed by water workup.
Next, tricarboxylic acid 6 was converted into tris(ester) 4
in a very good yield (96–98%, see Exp. Section, Method B)
Recently, quinoide 7 was reported as the only product to
and then into the title product. This two-step sequence (see result from the oxidative decarboxylation of trityl 5 with
Scheme 1, steps f and d) could potentially complete an ef- nicotinamide adenine dinucleotide phosphate hydride
ficient protocol that is capable of affording trityl 5 in good (NADPH)/O2, which was catalyzed by rat, pig, and human
overall yield with high reproducibility by using simple and liver microsomes,[16] and the reaction of 5 with superoxide,
highly scalable procedures.
which was generated by a xanthine/xanthine oxide sys-
However, a shorter synthetic procedure that gave the Fin- tem.[16,17] The rationale for this reaction involves the attack
·–
land trityl directly from triacid 6 through a one-pot opera- of the O2 at the para carbon of the TAM aryl ring fol-
tion[14] seemed reasonable and eventually practical. Litera- lowed by the loss of CO2 from the resulting diamagnetic
ture searches revealed only one method suitable for these intermediate and a proton-catalyzed heterolytic cleavage of
purposes. It involved the treatment of various bulky tris- the O–O bond of the hydroperoxide group.[16,17]
(tetrathiaaryl)methanols with trifluoroacetic acid, and the
The absence of superoxide or the source of any other
corresponding trityl radicals were isolated quantitatively af- peroxide species means that the generation of quinoide 7 by
ter a standard water workup procedure.[5,11,15] Nothing cer- the mechanism described in literature, and above, is highly
tain is known about the mechanistic details of this reaction, improbable in our case. A plausible explanation for the si-
apart from the statement that “this formal one-electron re- multaneous formation of trityl 5 and diamagnetic quinoide
duction of the central carbon was quite surprising”.[11] This 7 might follow from what is known about the ready reaction
conclusion is still more convincing if one takes into account of sterically hindered trityl cations with nucleophiles.[18]
the absence of evident and indubitable reductants for the Typically, they attack aryl rings at the para position to give
initial reagents. Again, a priori, it seemed unreasonable to 4-methylenecyclohexa-2,5-diene intermediates analogous to
predict that the reaction would generate an intermediate 9 (see Scheme 3). Very recently C. Decroos et al. reported
that could play the part of a reducing agent.
the formation of trityl radicals through an electron transfer
To gain better insight into mechanistic details of this pro- (ET) reaction between intermediate methylenecyclohexa-
cess, we attempted a series of reactions between triaryl- 2,5-dienes and trityl cations, which were generated in situ
methanol 6 and TFA. Some reaction conditions were by oxidation of trityl 5 either by potassium hexachloro-
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V. M. Tormyshev et al.
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Scheme 3. Proposed mechanism for formation of quinone methide 7 and TAM 5 through a two-step sequence of ET reactions.
iridate(IV)[19] or hydrogen peroxide in the presence of per-
oxidases (horse radish peroxidase, lactoperoxidase, prosta-
glandin synthase, and other hemeproteins).[20]
This fruitful concept of ET reactions with trityl cations
participating as an oxidant provides the missing link to in-
terpret our results as shown in Scheme 3. The explanation
involves the reaction of cation 8 with water to yield interme-
diate cyclohexadiene 9. The decarboxylation of 9 followed
by oxidation with cation 8 (or vice versa) gives trityl 5 and
transient trityl 10. The latter should be readily oxidized by
cation 8 along with the eventual formation of quinoide 7
and the next crop of trityl 5. The overall balanced reaction
follows Equation (1).
3 8 + H2O Ǟ 2 5 + 7 + 3 H+ + CO2
(1)
This proposed mechanism predicts the yield of trityl 5 to
be below 66.7% and the ratio of trityl to quinoide to be Scheme 4. Synthesis of trityl 11 and quinoide 12 by treatment of
triarylmethanol 3 with TFA followed by water workup.
strictly equal to 2:1. The first part of this prediction is in
good agreement with our experimental data. The second
one is notably in disagreement with the experiment. It is
We may legitimately assume that TFA acts as a typical
obvious that the high polarity of both products presents a acidic reagent, which selectively generates trityl cations as
severe problem for their quantitative isolation through stan- other strong acids do. The assumption of the cationic na-
dard preparative means (e.g., column chromatography), ture of the primary product that results from the treatment
and, thus, for an accurate evaluation of the product distri- of triarylmethanols 3 and 6 with TFA implies two impor-
bution. Searching for a more suitable model, we examined tant consequences. First, the reduction of intermediate cat-
less polar triarylmethanol 3. Analogously, the treatment of ion 8 with sufficiently strong reducing reagent must result
3 with TFA and the subsequent quenching of the hypotheti- in trityl 5 as the only product and completely restrain the
cal carbocation with water afforded a mixture of two major undesirable side reaction that leads to the quinoide. Indeed,
products (see Scheme 4), both of which were isolated by as predicted, the addition of SnCl2 (0.5 equiv.) to a TFA
column chromatography with minimal loss.[21] Trityl 11 and solution of 6 (see Scheme 1) smoothly afforded the Finland
quinoide 12 were obtained in ratio of 2.17:1, which thus trityl (5) as the only product isolated in 96% yield (see Exp.
confirmed the plausibility of Scheme 3. Replacing TFA Section, Method D). Second, replacing water with alterna-
with alternative strong acids such as CF3SO3H and HBF4 tive nucleophiles must result in the formation of asymmetri-
etherate gave similar results of 2.13:1 and 2.07:1, respec- cal monosubstituted trityls along with a symmetrical one.
tively.
If the addition of the nucleophile to the para carbon atom
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Generation of Trityl Radicals by Nucleophilic Quenching of Cations
of the cation is slower than the further oxidation of the are useful for numerous applications in biology, spec-
intermediate cyclohehadiene, the reaction must give an troscopy, and material science. A detailed study of this intri-
equimolar mixture of the two forms of the trityl, however, guing chemistry is currently underway and will be reported
that is, only if the asymmetrically substituted trityl is suffi- in the next paper.
ciently stable towards further oxidation with the triaryl-
methyl cation.
The support of this hypothesis followed from an experi-
Conclusions
ment, in which the carbocation generated from 3 and TFA
The reaction of nucleophiles with tris(2,3,5,6-tetra-
was quenched with diethylamine (5 equiv.). The crude prod-
thiaaryl)methyl cations, which were generated from the cor-
responding triarylmethanols in the presence of strong acids,
uct was composed of the known trityl 11 and asymmetrical
monosubstituted trityl 15, which was easily detectable by
resulted in trityl radicals, as the products of a one-electron
the characteristic hyperfine splitting in the ESR spectrum,
reduction of carbocations. Depending on the nature of the
that is, a quartet and broad triplet, respectively (see Sup-
nucleophile, the only byproducts were either diamagnetic
porting Information). Trityls 11 and 15 were isolated in
quinone methides or asymmetrical monosubstituted trityl
47% and 42% yields, respectively, and their ratio was close
radicals. The latter is available on a preparative scale. A
to the predicted 1:1 ratio (see Scheme 5 for a summary of
the arguments stated above and the literature data[19,20]).
revised protocol for the large-scale synthesis of the Finland
trityl is reported. The improved version of the synthesis has
the advantage of simplicity, high reproducibility, and a no-
table increase in the overall yield.
Experimental Section
1
General Methods: The H and 13C NMR spectroscopic data were
recorded with
a
Bruker AV-400 spectrometer (1H NMR,
400.134 MHz; 13C NMR, 100.624 MHz) and a Bruker AV-600
spectrometer (1H NMR, 600.302 MHz; 13C NMR, 150.964 MHz).
Chemical shifts (δ scale) are given in ppm with reference to the
residual signals of CDCl3 (1H NMR, 7.26 ppm; 13C NMR
77.16 ppm), [D6]DMSO (1H NMR 2.50 ppm; 13C NMR
39.52 ppm), or CD3OD (1H NMR, 3.31 ppm, 13C NMR,
49.00 ppm). IR spectra were recorded with a Bruker Tensor 27 and
Bruker Vector 22 FTIR spectrometers, and KBr pellets were used.
Wavenumber values are given in cm–1. UV/Vis absorption spectra
were obtained with a Varian Cary 5000 UV/Vis/NIR spectrometer,
and the data were collected using dilute solutions (0.1 mm) in
quartz spectroscopy cells. The ESR spectra were recorded with a
Bruker ELEXSYS E540 spectrometer (microwave power of 2 mW,
modulation frequency of 100 KHz, and modulation amplitude of
0.003 mT). Electrospray ionization mass spectra (ESI-MS) were re-
corded with a hybrid quadrupole/time-of-flight Bruker micrOTOF-
Q spectrometer. Methanol used as the solvent, and the spectra were
scanned in the m/z range of 100–3000 in the positive and negative
ionization modes. Nitrogen was used as the drying gas at 220 °C
and at a flow rate of 4 Lmin–1. The nebulizer pressure was set to
1.0 bar. The capillary voltage was set at –4.0 kV. Sample solutions
were infused into the ESI source by using a LC Agilent 1200 in the
FIA mode (Flow Injection Analysis, 2–3 μL at a flow rate for
CH3OH of 0.1 mLmin–1). MALDI-TOF mass spectra were re-
Scheme 5. Proposed mechanism for formation of trityl 11 along
with monosubstituted trityl 15.
The proposed mechanism implies that a large excess
amount of the nucleophile and/or its high reactivity could
potentially channel the reaction to the preferential forma-
tion of intermediate 14 and, thus, hinder the pathway lead-
ing to trityl 11. Depending on stability of 14, it might be
isolated as such or in the form of trityl 15. In an attempt
to provide the above conditions for the slow oxidation of
intermediate 14 with cation 13, that is, k1[HNEt2] ϾϾ corded with an autoflex III MALDI-TOF mass spectrometer
(Bruker Daltonics, Germany), which was equipped with a pulsed
nitrogen laser (337 nm) in a positive reflectron mode. Ions formed
by a laser beam were accelerated to 20 keV kinetic energy. The final
spectra were obtained by the accumulation of a 1500 single laser
shot spectrum. The solution of 2,5-dihydroxybenzoic acid (DHB)
in acetonitrile (50 mg/mL) was used as a matrix. A sample solution
in chloroform was mixed with the same volume of the matrix solu-
tion. Approximately 1 μL of the resulting solution was deposited
on the 384 ground steel target plate and allowed to dry before being
introduced into the mass spectrometer. External calibration in the
k2[13] (see Scheme 5), a DCM solution of cation 13, which
was generated from 3 and CF3SO3H, was added slowly
through a syringe to large excess amount of diethylamine
in DCM. The standard workup, which provided the expo-
sure of the crude product to atmospheric oxygen, gave the
expected product 15 in the high isolated yield of 82%.
In preliminary experiments, we have extended this ap-
proach to other nucleophiles and clearly showed the poten-
tial for the preparative synthesis of a wide variety of new
diversely substituted persistent triarylmethyl radicals, which positive mode was done by using Peptide Calibration Standard II
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V. M. Tormyshev et al.
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(Part No. 222570, Bruker Daltonics, Germany). Mass accuracy of
approximately 0.1% was usually achieved. Mass spectra were pro-
cessed by flexAnalysis 2.4 software (Bruker Daltonik GmbH, Ger-
many). Analytical HPLC analyses were carried out with an Agilent
1100 Series instrument, which was equipped with a ZORBAX
Eclipse XDB C8 column [methanol and then methanol with the
addition of 0.1% (v/v) trifluoroacetic acid]. Preparative column
chromatography was performed using 60–200 μm silica gel, which
was purchased from Acros. Chemicals were purchased from Ald-
rich and Acros and were used without further purification.
2955 (m), 2920 (m), 2910 (m), 1450 (s), 1377 (s), 1364 (s), 1344 (m),
1248 (m), 1167 (s), 1148 (s), 787 (s), 760 (s) cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 1.67 (s, 9 H, CH3), 1.72 (s, 9 H, CH3), 1.80
(s, 9 H, CH3), 1.822 (s, 9 H, CH3), 6.22 (s, 1 H, OH), 7.17 (s, 3 H,
CH) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.74 (CH3), 29.29
(CH3), 32.38 (CH3), 34.93 (CH3), 63.49 (SCS), 64.18 (SCS), 83.79
(COH), 118.30 (CH), 131.99 (C), 137.39 (C), 137.98 (C), 138.46
(C), 139.36 (C) ppm.
Tris(8-ethoxycarbonyl-2,2,6,6-tetramethylbenzo[1,2-d;4,5-dЈ]bis[1,3]-
dithiol-4-yl)methanol (4): Compound 4 was prepared by analogy to
a recently published literature protocol.
1,2,4,5-Tetra-tert-butylthiobenzene (1): Compound 1 was prepared
by analogy to a known literature method.[10] Off-white powder
(71% yield); m.p. 146–151 °C. C22H38S4 (430.78): calcd. C 61.34,
Method A:[8] To a stirred suspension of 3 (0.886 g, 1 mmol) and
freshly distilled TMEDA (1.16 g, 10 mmol) in n-hexane (2 mL) at
0 °C (bath temperature) was added dropwise nBuLi (2.5 m in hex-
ane, 4 mL, 10 mmol) over 30 min under argon. After the mixture
was stirred at room temp. for 3.5 h, anhydrous toluene (4 mL) was
added. The resulting dark brown gel was stirred at room temp.
for an additional 1 h and then poured into cooled (–15 °C, bath
temperature) freshly distilled diethyl carbonate (4.75 g, 40 mmol)
diluted with toluene (10 mL). The cooling bath was removed, and
the stirring was continued overnight at room temp. Saturated aque-
ous NaH2PO4 (5 mL), water (10 mL), and ether (25 mL) were
added. The organic phase was separated, filtered through a short
plug of silica, and concentrated in vacuo. The crude product was
purified by column chromatography on silica gel (dichloromethane/
hexane, from 1:6 to 1:1) followed by recrystallization from acetoni-
trile (15 mL) to afford 4 (0.352 g, 32%) as a lemon yellow powder
[contained residual acetonitrile (6–8 mol-%)]; m.p. Ͼ270 °C (grad-
ually decomposed, turned black). HPLC purity: Ͼ95 %.
C46H52O7S12 (1101.63): calcd. C 50.15, H 4.76; found C 50.42, H
1
H 8.89; found C 61.12, H 8.72. H NMR (400 MHz, CDCl3): δ =
1.38 (s, 36 H, CH3), 7.95 (s, 2 H, CH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 31.24 (CH3), 48.11 (CCH3), 139.24, 144.70 ppm.
2,2,6,6-Tetramethylbenzo[1,2-d;4,5-dЈ]bis[1,3]dithiole (2): To
a
stirred suspension of 1 (10.78 g, 25 mmol) in chloroform (30 mL)
were added acetone (17.5 mL, 240 mmol), d-(+)-10-camphor-
sulfonic acid (1.16 g, 5 mmol), and BF3 (48 wt.-% BF3 in ether,
9.8 mL, 75 mmol). The flask was flushed with argon and connected
to a reflux condenser that was equipped with a mineral oil bubbler.
The mixture was then stirred at 75–80 °C for 24 h. The cooled mix-
ture was poured into water (30 mL), and the resulting biphasic li-
quid was neutralized to pH = 7 by the portionwise addition of
NaOH (2 n solution). The organic phase was separated, and the
water phase was extracted with chloroform (3ϫ10 mL). The com-
bined organic layers were washed with brine, filtered through a
short silica plug, and concentrated in vacuo. The resulting solid
was heated at reflux in methanol (35 mL) for 30 min. The mixture
was then filtered, washed with methanol/hexane (4:1 v/v, 3ϫ5 mL),
and dried in vacuo to give 2 (6.65 g, 93%) as a fine pale yellow
precipitate; m.p. 145–147 °C. C12H14S4 (286.48): calcd. C 50.31, H
4.46. IR (KBr): ν = 3354 (m), 2974 (m), 2915 (w), 1707 (s), 1450
˜
(m), 1368 (m), 1319 (m), 1246 (s), 1230 (s), 1101 (m), 1024
1
(m) cm–1. H NMR (400 MHz, CDCl3): δ = 1.43 (t, J = 7.1 Hz, 9
H, OCH2CH3), 1.63 (s, 18 H, CH3), 1.72 (s, 9 H, CH3), 1.74 (s, 9
H, CH3), 2.09 (s, approximately 0.21 H, acetonitrile), 4.41 (m, 6 H,
OCH2),[22] 6.75 (s, 1 H, OH) ppm. 13C NMR (100 MHz, CDCl3):
δ = 14.41 (CH2CH3), 28.80 (CH3), 29.36 (CH3), 32.01 (CH3), 33.98
(CH3), 61.01 (SCS), 61.09 (SCS), 62.49 (OCH2CH3), 84.46 (COH),
121.45 (C), 134.14 (C), 139.40 (C), 140.50 (C), 141.59 (C), 142.00
(C), 166.34 (CO2Et) ppm.
4.93, S 44.77; found C 51.13, H 4.96, S 44.36. IR (KBr): ν = 2990
˜
(m), 2964 (s), 2928 (m), 1448 (s), 1423 (s), 1381 (m), 1364 (s), 1329
(s), 1258 (s), 1167(s), 1149(s), 1091 (s), 851 (s), 640 (m), 407
1
(m) cm–1. H NMR (400 MHz, CDCl3): δ = 1.88 (s, 12 H, CH3),
7.02 (s, 2 H, CH) ppm. 13C NMR (100 MHz, CDCl3): δ = 31.41
(CH3), 65.88 (CCH3), 116.96, 135.84 ppm.
Method B:[12] A solution of triacid 6 (3.055 g, 3 mmol) and dry
triethylamine (1.820 g, 18 mmol) in anhydrous chloroform (20 mL)
was stirred at room temp. for 10 min. To the resulting homogen-
eous solution was added a solution of SOCl2 (3.580 g, 30 mmol) in
chloroform (5 mL) dropwise over 20 min. The mixture was heated
at reflux for 2.5 h, stirred overnight at room temp., and then con-
centrated to dryness to give an orange-yellow cake. Anhydrous eth-
anol (15 mL, 255 mmol), chloroform (5 mL), and pyridine (0.395 g,
5 mmol) were added. The resulting mixture was stirred at 60 °C for
4 h and then overnight at room temp. After removal of solvents in
vacuo, chloroform (45 mL) and water (20 mL) were added to the
solid residue. The organic phase was separated, washed with HCl
(0.1 m aqueous solution, 15 mL) and water (3ϫ10 mL), filtered
through a short silica plug, and concentrated in vacuo to give prod-
uct 4 (3.240 g, 98%) as a lemon yellow precipitate.
Tris(2,2,6,6-tetramethylbenzo[1,2-d;4,5-dЈ]bis[1,3]dithiol-4-yl)meth-
anol (3): A suspension of 2 (10.00 g, 35 mmol) and sodium hydride
(60 wt.-% paste in mineral oil, 0.140 g, 3.5 mmol) in anhydrous
ether (100 mL) was stirred overnight at room temp. under argon.
nBuLi (2.5 m in hexane, 15.4 mL, 38.5 mmol, 1.1 equiv.) was added
dropwise over 1 h. The thick slurry was stirred for 24 h, and then
a solution of freshly distilled diethyl carbonate (1.32 g, 11.2 mmol,
0.32 equiv.) in anhydrous hexane (4.5 mL) was added over 4 h. The
resulting orange mixture was stirred at room temp. for 48 h and
then quenched by the dropwise addition of ethanol (2 mL) followed
by NH4Cl (2 m solution, 25 mL). Dichloromethane (20 mL) was
added, and the organic layer was separated. The water phase was
extracted with additional CH2Cl2 (2ϫ10 mL). The combined or-
ganic layers were washed with HCl (0.2 m solution), filtered
through a short plug of silica, and concentrated in vacuo. The re-
sulting solid was heated at reflux in a mixed solvent of CCl4
(24 mL) and hexane (24 mL) for 15 min. After cooling to room
temp., the solid powder was collected on a filter, washed with a
CCl4/hexane (1:1 v/v, 3 ϫ 5 mL), and dried in vacuo to give 3
(7.43 g, 72% based on arene 2) as a fine pale yellow precipitate;
m.p. Ͼ280 °C (gradually turned black, decomposition). HPLC pu-
rity: Ͼ95%. C37H40OS12 (885.44): calcd. C 50.19, H 4.55, S 43.45;
Tris(8-carboxy-2,2,6,6-tetramethylbenzo[1,2-d;4,5-dЈ]bis[1,3]dithiol-
4-yl)methyl (5): Compound 5 was prepared from trityl alcohol 4 by
analogy to a literature procedure.[8]
Method C: To a stirred solution of 4 (0.551 g, 0.5 mmol) in dichloro-
methane (15 mL) was added a solution of CF3SO3H (1.125 g,
7.5 mmol) in anhydrous acetonitrile (3 mL) dropwise over 5 min
found C 49.88, H 4.54, S 42.94. IR (KBr): ν = 3366 (m), 2972 (m), under argon. After the mixture was stirred at room temp. for
˜
3352
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Generation of Trityl Radicals by Nucleophilic Quenching of Cations
10 min, a solution of SnCl2 (0.095 g, 0.5 mmol) in anhydrous tetra-
hydrofuran (THF, 8 mL) was added. The resulting dark brownish-
green solution was stirred at room temp. under argon for 10 min
and then was quenched with saturated aqueous NaH2PO4 (30 mL).
The mixture was diluted with chloroform (15 mL), and the re-
sulting solution was stirred vigorously for 2 min. The organic layer
was separated, washed with brine (10 mL) and then water
(2ϫ10 mL), dried with MgSO4, filtered, and concentrated in vacuo
to give the tris(ester) trityl as a black cake. Ethanol (5 mL), dioxane
(5 mL), and a solution of KOH (0.280 g, 5 mmol) in water (4 mL)
were added. The mixture was stirred at 50 °C under argon for 2 h,
and then all of the solvents were removed in vacuo. Water (40 mL)
was added. After stirring the resulting mixture overnight at room
temp. under argon, the resulting homogeneous deep green solution
was filtered through a paper filter, and the filtrate was acidified by
the addition of HCl (2 m solution) to pH = 2.5–3. A viscous deep
brown-colored gel resulted, which was left overnight at 5 °C under
argon until the coagulation was complete. The resulting solid was
collected on a filter, washed with HCl (0.1 m solution, 3ϫ5 mL)
and then water, and dried in vacuo to give trityl 5 (0.506 g, 92%)
as a brownish-black fine powder. MS (ESI): calcd. for C40H38O6S12
[M – H]– 997.932; found 997.942; calcd. for C40H37O6S12 [M –
tion and then a thick pale brown slurry. To lessen the viscosity,
anhydrous toluene (24 mL) was added by syringe. The resulting
fluent gel was stirred for 30 min and then transferred to solid car-
bon dioxide (350–500 g) that was soaked in anhydrous toluene
(100 mL). The mixture was left to attain ambient temperature. The
solvents and TMEDA were evaporated in vacuo. The resulting so-
lid cake was triturated with toluene (20 mL), which then was evapo-
rated again to remove the residual TMEDA. Methyl tert-butyl
ether (50 mL), water (150 mL), and NaOH (2 m solution, 20 mL)
were added to the residue. The biphasic mixture was vigorously
shaken and transferred to a separatory funnel, to which brine
(60 mL) was added. The water phase was separated, and the or-
ganic phase was extracted in the order of water (1ϫ30 mL), NaOH
(2 m solution, 1 ϫ2 mL), and brine (1 ϫ10 mL). The combined
water extracts were left at room temp. until there was complete
precipitation of the solid impurities (typically overnight). The mix-
ture was then filtered through slow-filtering paper (e.g., Whatman
Grade 50) and acidified to pH = 2 by the slow addition of hydro-
chloric acid (4 m aqueous solution) to give a lemon yellow slurry.
After 5 h, the solid was collected on a filter, washed with HCl (0.1 m
aqueous solution, 5 ϫ 20 mL) and water (50 mL), and dried in
vacuo. The dry residue was heated at reflux in acetonitrile (25 mL)
2H]2– 498.462; found 498.464. IR (KBr): ν = 2958 (m), 2920 (m), for 20 min. After standing at 5 °C for 2 h, the solid was collected
˜
1691 (s), 1452 (m), 1385 (m), 1366 (m), 1232 (s), 1169 (m), 1149 (m), on a filter, washed with cold acetonitrile (5ϫ3 mL), and dried in
1109 (m), 864 (m), 725 (m) cm–1. ESR: singlet; linewidth, 226 mG
vacuo to give 6 (4.479 g, 62%) as a lemon yellow solid [product
for solution in contact with atmospheric air; g = 2.0056 (0.5 mm in may have contained residual acetonitrile (30–40 mol-%, 1.5–2 wt.-
water, pH = 8.5). The paramagnetic purity for the radical was found
to be Ͼ95% in experiment with 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO) used as a standard. HPLC purity Ͼ97%.
%)]; m.p. Ͼ280 °C (gradually turned black, decomposition). HPLC
purity Ͼ95%. C40H40O7S12 (1017.47): calcd. C 47.21, H 3.96, S
37.82; found C 46.91, H 4.12, S 37.36. MS (ESI): calcd. for
C40H39O7S12 [M – H]– 1014.935; found 1014.946. IR (KBr): ν =
˜
Method D: A suspension of 6 (2.040 g, 2.00 mmol) in freshly dis-
tilled TFA (12 mL) and DCM (12 mL) was stirred at room temp.
under argon for 5 h. To the resulting greenish-brown solution was
added slowly by syringe a solution of SnCl2 (0.190 g, 1.00 mmol)
2963 (m), 2918 (m), 2860 (m), 1688 (s), 1508 (m), 1453 (m), 1431
(m), 1367 (m), 1317 (m), 1261 (m), 1223 (s), 1167 (m), 727 (w) cm–1.
1H NMR (400 MHz, [D6]DMSO): δ = 1.59 (s, 9 H, CH3), 1.62 (s,
9 H, CH3), 1.69 (s, 9 H, CH3), 1.72 (s, 9 H, CH3), 2.07 (s, 0.8–1.2
H, acetonitrile), 6.79 (s, 1 H, OH) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 27.52 (CH3), 28.56 (CH3), 31.35 (CH3), 33.92 (CH3),
60.72 (SCS), 60.80 (SCS), 83.59 (COH), 122.11 (C), 133.40 (C),
138.33 (C), 139.87 (C), 140.60 (C), 140.94 (C), 167.06 (CO2H) ppm.
[23]
in anhydrous THF (5 mL). The resulting thick brown slurry
was stirred overnight at room temp. under argon. The mixture was
poured into water (50 mL). The water phase was neutralized to pH
= 3–3.5 by the slow addition of NaOH (2 m solution). After the
addition of THF (80 mL), the organic phase was separated, and the
water phase was extracted with THF (3ϫ10 mL). The combined
organic extracts were washed with brine (4ϫ10 mL) and concen-
trated in vacuo. The solid residue was dissolved in a mixture of
water (200 mL) and NaOH (2 m solution, 20 mL). Brine (100 mL)
was added to resulting deep-green solution, which was left for 2 h
at room temp. The solution was filtered through slow-filtering pa-
per, and the filtrate was acidified to pH = 2–3 by the addition of
HCl (2 m aqueous solution) to give a brown gel. After 5 h, the solid
was collected on a filter, washed with HCl (0.1 m aqueous solution,
5ϫ20 mL) and water (2ϫ20 mL), and dried in vacuo to give trityl
5 (1.920 g, 96%) as a brownish-black fine powder. MS (ESI): calcd.
Tris(8-carboxy-2,2,6,6-tetramethylbenzo[1,2-d;4,5-dЈ]bis[1,3]dithiol-
4-yl)methyl (5) and Quinone Methide 7: A suspension of 6 (0.375 g,
0.37 mmol) in freshly distilled TFA (4 mL) was stirred for 16 h at
room temp. under argon.[24] The deep colored greenish-brown solu-
tion was concentrated in vacuo to give a black cake. The cake was
dissolved in NaOH (2 m solution, 5 mL, 10 mmol), and the re-
sulting solution was diluted with water (10 mL) to afford a reddish-
brown solution.[25] The addition of brine (10 mL) resulted in the
formation of an abundant amount of a fine precipitate. The mix-
ture was left under argon for 4 h and then filtered through slow-
filtering paper. The deep green clear filtrate was acidified to pH =
3 by the addition of HCl (2 m solution) to give 5 (0.206 g, 56%),
which was isolated as reported above. The solid material collected
on the filter and was washed with water/brine (1:1 v/v, 3ϫ5 mL).
The solid was then dissolved in acidified methanol [concentrated
HCl (25 μL) in methanol (50 mL)]. The resulting deep purple solu-
tion was concentrated in vacuo, and the crude product was purified
by column chromatography on silica gel (dichloromethane/meth-
anol, from 20:1 to 3:1 v/v) to afford quinoide 7 (0.078 g, 22%) as
a reddish-black powder; m.p. Ͼ280 °C (decomposition). Data for
7: MS (ESI): calcd. for C39H37O5S12 [M – H+]– 968.929; found
–
for C40H38O6S12 [M – H]– 997.932; found 997.90. UV/Vis (meth-
anol): λmax (ε, L mol–1 cm–1) = 267 (47000), 402 (17500), 483
(19400) nm. ESR: singlet; linewidth, 94 mG for deoxygenated water
solution; g = 2.0056 (1.0 mm in water, pH = 8.0). MS (ESI) and
ESR spectra are presented in the Supporting Information.
Tris(8-carboxy-2,2,6,6-tetramethylbenzo[1,2-d;4,5-dЈ]bis[1,3]dithiol-
4-yl)methanol (6): Compound 6 was prepared by analogy to the
literature protocol.[12] To a stirred suspension of 3 (6.265 g,
7.10 mmol) in n-hexane (7 mL) and freshly distilled anhydrous
TMEDA (25 mL) cooled to –78 °C under argon was added by sy-
ringe n-butyllithium (2.5 m in hexane, 28.4 mL, 0.071 mol, 968.935. IR (KBr): ν = 2957 (m), 2920 (s), 2851 (m), 1686 (m),
˜
10 equiv.) slowly over 30 min. After stirring for 20 min, the cooling
bath was removed, and the reaction was stirred at room temp. for
2 h 30 min. The mixture gradually changed to a dark brown solu-
1659 (m), 1603 (s), 1585 (s), 1495 (m), 1452 (s), 1385 (s), 1366 (s),
1231 (s), 1150 (s), 1105 (m), 733 (m) cm–1. UV/Vis (methanol): λmax
(ε, L mol–1 cm–1) = 276 (38100), 369 (11700), 477 (9600), 529
Eur. J. Org. Chem. 2013, 3347–3355
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3353

V. M. Tormyshev et al.
FULL PAPER
(10800) nm. 1H NMR (400 MHz, [D6]DMSO): δ = 1.57 (s, 6 H,
with aqueous ammonia) to give pure 11 (0.062 g, 47%) and 15
CH3), 1.63 (s, 6 H, CH3), 1.69 (s, 6 H, CH3), 1.71 (s, 6 H, CH3), (0.057, 42%) as a black powder (bluish-green in DCM solution).
1
1.72 (s, 6 H, CH3), 1.76 (s, 6 H, CH3) ppm. H NMR (600 MHz, Data for 15: MS (ESI): calcd. for C41H49NS12 [M + H]+ 939.051;
CD3OD): δ = 1.64 (s, 6 H, CH3), 1.72 (s, 6 H, CH3), 1.74 (s, 6 H, found 939.040. MALDI-TOF: calcd. for C41H48NS12 [M]+ 938.043;
CH3), 1.76 (s, 6 H, CH3), 1.82 (s, 6 H, CH3), 1.85 (s, 6 H, found 938.00. IR (KBr): ν = 2959 (s), 2922 (s), 2912 (s), 1450 (s),
˜
CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 29.95 (CH3),
1381 (s), 1363 (s), 1251 (s), 1167 (s), 1148 (s), 853 (m), 704 (m) cm–1.
28.27 (CH3), 30.45 (CH3), 31.18 (CH3), 33.35 (CH3), 34.52 (CH3), UV/Vis (CH2Cl2): λmax (ε, Lmol–1 cm–1) = 270 (61100), 322 (16200),
60.97 (SCS), 61.67 (SCS), 62.63 (SCS), 127.30 (C), 128.49 (C), 445 (9120) nm. ESR: broad 1:2:1 triplet αH = 2.29 G; linewidth,
131.29 (C), 137.08 (C), 138.94 (C), 140.44 (C), 141.79 (C), 142.89 609 mG for 1 mm solution in DCM; g = 2.0055. Spectra of trityl
(C), 157.40 (C), 169.07 (CO), 171.55 (CO) ppm. 13C NMR
(150 MHz, CD3OD): δ = 29.50 (CH3), 31.08 (CH3), 32.24 (CH3),
33.25 (CH3), 34.66 (CH3), 62.86 (SCS), 63.77 (SCS), 64.00 (SCS),
129.30 (C), 130.44 (C), 131.01 (C), 139.22 (C), 140.36 (C), 140.99
(C), 141.59 (C), 143.82 (C), 145.54 (C), 157.39 (C), 173.96 (CO),
174.63 (CO) ppm. Spectra of quinoide 7 are given in Supporting
Information.
15 are presented in the Supporting Information.
Alternative Preparation for Trityl 15: A solution of 3 (0.132 g,
0.146 mmol) in anhydrous dichloromethane (3 mL) and CF3SO3H
(0.044 g, 0.293 mmol) was stirred at room temp. for 2 h under ar-
gon. The resulting deep green solution was added by syringe slowly
over 30 min to
a stirred solution of diethylamine (0.320 g,
4.38 mmol) in DCM (1 mL). The homogeneous solution was
stirred overnight at room temp., and then water (6 mL) was added.
The mixture was stirred and left in the air for 30 min. The organic
phase was separated, and the water phase was extracted with
CH2Cl2 (3ϫ3 mL). The combined organic extracts were filtered
through a short cotton plug and concentrated in vacuo. Column
chromatography on silica gel (DCM/hexane, 1:1 v/v and then
DCM) afforded trityl 15 (0.111 g, 82%) as the only product.
Tris(2,2,6,6-tetramethylbenzo[1,2-d;4,5-dЈ]bis[1,3]dithiol-4-yl)methyl
(11) and Quinone Methide 12: A solution of 3 (0.200 g, 0.226 mmol)
in anhydrous dichloromethane (2 mL) and freshly distilled TFA
(2 mL)[26] was stirred at room temp. overnight under argon. The
deep green solution was concentrated in vacuo to give a black cake.
The cake was dissolved in dichloromethane (4 mL), and then water
(2 mL) was added. The mixture was stirred for 7 h under argon,
and the green organic solution slowly changed to a deep brown
color. The organic phase was separated, and water phase was ex-
tracted with DCM (3ϫ2 mL). The combined organic extracts were
filtered through a short cotton plug and concentrated in vacuo.
Column chromatography on silica gel (dichloromethane/hexane,
from 1:1 to 5:1) afforded trityl 11 (0.115 g, 58.6%) as a greenish-
black powder (green in DCM solution) and quinoide 12 (0.054 g,
27.0%) as a reddish-black powder. Data for 11: MS (ESI): calcd.
for C37H39S12 [M]+ 866.970; found 866.964. MALDI-TOF: m/z =
Supporting Information (see footnote on the first page of this arti-
cle): TLC analyses of crude products obtained from triarylmethan-
ols 6 and 3. MS (ESI), 1H and 13C NMR, and UV/Vis spectro-
scopic data for quinoides 7 and 12. MS (ESI), MALDI-TOF, ESR,
and UV/Vis spectroscopic data for trityls 11 and 15. MS (ESI),
ESR, and UV/Vis spectroscopic data for trityl 5 (Method D).
Acknowledgments
867.04. IR (KBr): ν = 2974 (m), 2954 (m), 2920 (m), 2910 (m),
˜
1452 (m), 1363 (s), 1342 (m), 1248 (s), 1169 (m), 1148 (s), 1103 (m),
849 (m), 644 (m) cm–1. UV/Vis (CH2Cl2): λmax (ε, Lmol–1 cm–1) =
273 (55300), 325 (22300), 443 (21500) nm. ESR: 1:3:3:1 quartet αH
= 2.27 G; linewidth, 258 mG for 1 mm solution in DCM; g =
2.0055. Spectra of trityl 11 are given in the Supporting Infor-
mation. Data for 12: m.p. Ͼ260 °C (decomposition). MS (ESI):
calcd. for C37H39OS12 [M + H]+ 882.965; found 882.964. IR (KBr):
The authors thank Drs. Leonid A. Shundrin and Denis A. Koma-
rov for recording the ESR spectra and Dr. V. V. Koval for the regis-
tration of the MALDI-TOF spectra. The authors wish to thank
Professor Michael K. Bowman (University of Alabama, USA), Dr.
Alexander M. Genaev and G. E. Sal’nikov for the helpful dis-
cussion and suggestions. This study was supported by The Russian
Foundation for Basic Research (project 13-04-00680A), The Minis-
try of Education and Science of the Russian Federation (project
8466) and the National Institute of Biomedical Imaging and Bioen-
gineering, National Institute of Health (NIH), grant number
5P41EB002034. NMR, IR, high resolution ESI-MS, and ESR ex-
periments were carried out in the Chemical Service Center of the
Siberian Branch of the Russian Academy of Sciences (RAS).
ν = 2957 (m), 2920 (s), 2912 (m), 1605 (s), 1468 (s), 1452 (s), 1364
˜
(s), 1252 (m), 1150 (s), 1090 (m), 1030 (m), 733 (m) cm–1. UV/Vis
(CH2Cl2): λmax (ε, Lmol–1 cm–1) = 273 (47600), 517 (18000) nm. 1H
NMR (600 MHz, CDCl3): δ = 1.70 (s, 6 H, CH3), 1.74 (s, 6 H,
CH3), 1.77 (s, 6 H, CH3), 1.79 (s, 6 H, CH3), 1.87 (s, 6 H, CH3),
1.89 (s, 6 H, CH3), 7.07 (s, 2 H, CH) ppm. 13C NMR (150 MHz,
CDCl3): δ = 29.66 (CH3), 30.07 (CH3), 31.42 (CH3), 31.66 (CH3),
31.88 (CH3), 33.63 (CH3), 62.81 (SCS), 64.72 (SCS), 65.86 (SCS),
119.08 (CH), 127.74 (C), 129.45 (C), 136.50 (C), 137.66 (C), 138.85 [1] a) S. Andersson, F. Radner, A. Rydbeck, R. Servin, L.-G. Wis-
trand, U. S. Patent 5530140, 1996; b) J. H. Ardenkjaer-Larsen,
I. Leunbach, PCT Int. Patent Appl. wo/9709633, 1997; c) S.
Andersson, F. Radner, A. Rydbeck, R. Servin, L.-G. Wistrand,
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(C), 139.04 (C), 141.22 (C), 144.05 (C), 153.20 (C), 172.85
(CO) ppm. Spectra of quinoide 12 are presented in the Supporting
Information.
Tris(2,2,6,6-tetramethylbenzo[1,2-d;4,5-dЈ]bis[1,3]dithiol-4-yl)methyl
(11) and Trityl 15: A solution of 3 (0.134 g, 0.150 mmol) in anhy-
drous dichloromethane (2 mL) and freshly distilled TFA (2 mL)
was stirred at room temp. overnight under argon. The deep green
solution was concentrated in vacuo to give a black cake. The cake
was dissolved in dichloromethane (4 mL), and the flask was flushed
with argon. A solution of diethylamine (0.055 g, 0.750 mmol) in
anhydrous DCM (2 mL) was added by a syringe. The resulting
green solution was stirred overnight and then concentrated in
vacuo. Trityls 11 and 15 were isolated by column chromatography
on silica gel (TFA in DCM, 1:1000 v/v and then DCM saturated
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During chromatography, trityl 11 and quinoide 12 separated
into compact sharp-edged bands. In addition, these bands were
deeply colored (e.g., see Supporting Information), and, there-
fore, it was easy to control the course of the chromatographic
isolation/purification.
[19]
[20]
[21]
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multiplet at δ = 4.41 ppm to give the AB system, which resulted
from the coupling of the geminal methylenic protons of the
ethoxy group at 4.39 (J = 10.8 Hz, 1 H, OCHaHb), 4.42 (J =
10.8 Hz, 1 H, OCHaHb) ppm.
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of the triarylmethane as the product of a formal two-electron
reduction. The presence of the triarylmethane is detected either
by MS (ESI) or the appearance of a characteristic series of
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1
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[14] In principle, this could be accomplished by following the earlier
method of a one-electron reduction of the carbocation that was
generated from 6 (for example, see Scheme 1, step d) by treat-
ing it with a strong protic or Lewis acid. Unfortunately, the
insolubility of the substrate in nonpolar solvents (e.g., chloro-
form or dichloromethane) obstructed the application of this
attractive approach.
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three singlet signals (1.6–1.75 ppm) in the H NMR spectrum
or four singlets (25–36 ppm) in the 13C NMR spectrum. There-
fore, it is strongly recommended to limit the amount of reduct-
ant to 0.5 equiv.
[24] Product distributions and their yields were shown to be inde-
pendent of the presence of atmospheric oxygen and the varia-
tion of reaction times over a range of 6–36 h.
[25] A drop of this solution was acidified to pH = 3. TLC analysis
of the sample obtained after removal of water clearly indicated
the two-component nature of the crude product (see Support-
ing Information).
[26] Also following the above protocol, trityl 11 and quinone me-
thide 12 were obtained by using other strong acids such as a
1:1 ethereal solution of HBF4 [3 equiv. in DCM (4 mL)] and
CF3SO3H [3 equiv. in DCM (4 mL)]. The yields and product
distribution were similar as those for the reaction with TFA.
Received: February 1, 2013
Published Online: April 15, 2013
Eur. J. Org. Chem. 2013, 3347–3355
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3355