Solvent-Free Synthesis of Diazocine

Article abstract of DOI:10.1055/s-0036-1590685

A convenient two-step synthesis of diazocine starting from 2-nitrotoluene is described. The first step, the oxidative dimerization of 2-nitrotoluene, is improved to 95% yield. The second step, the reductive azo cyclization, is performed as a solvent-free reaction with lead powder in a ball mill (51% yield). As a reference, the previously described azo cyclization with Zn/Ba(OH) ₂ is investigated in detail. The results explain why in previous experiments the yields are low and extremely dependent on the reaction conditions. In view of potential applications in photopharmacology, we checked the stability under reducing conditions. Diazocine does not react with glutathione, indicating intracellular stability.

Full text of DOI:10.1055/s-0036-1590685

SYNTHESIS
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2017, 49, A–E
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W. Moormann et al.
Paper
Synthesis
Solvent-Free Synthesis of Diazocine
Widukind Moormann
Daniel Langbehn
Rainer Herges*
Otto Diels Institute for Organic Chemistry, University of Kiel, Otto-Hahn-Platz 4,
24118 Kiel, Germany
rherges@oc.uni-kiel.de
Dedicated to Professor Herbert Mayr on the occasion of his 70th birthday
Received: 17.05.2017
Accepted after revision: 29.06.2017
Published online: 11.07.2017
fits into the binding site of the receptor. Diazocines, howev-
er, are more stable in their Z state, and could be adminis-
tered in their inactive form. At the site of illness, the drug
would be switched on with light with high spatiotemporal
control. Several examples prove the practicability of diazo-
cines in biochemical applications. Peptides and DNA
strands with switchable conformations have been prepared
by incorporation of diazocines, and spatiotemporal regula-
tion of DNA functions has been suggested.6,7 However, the
synthesis of diazocines proceeds with notoriously poor
yields and low reproducibility. We therefore optimized and
investigated in detail the most frequently used preparation
method, i.e., the oxidative coupling of 2-nitrotoluene and
the reduction of 2,2′-dinitrodibenzyl with Zn powder and
Ba(OH)2. Based on the mechanistic information, we have
developed a convenient, reliable, and solvent-free synthesis
of diazocine.
DOI: 10.1055/s-0036-1590685; Art ID: ss-2017-z0341-op
Abstract A convenient two-step synthesis of diazocine starting from
2-nitrotoluene is described. The first step, the oxidative dimerization of
2-nitrotoluene, is improved to 95% yield. The second step, the reductive
azo cyclization, is performed as a solvent-free reaction with lead pow-
der in a ball mill (51% yield). As a reference, the previously described azo
cyclization with Zn/Ba(OH)2 is investigated in detail. The results explain
why in previous experiments the yields are low and extremely depen-
dent on the reaction conditions. In view of potential applications in
photopharmacology, we checked the stability under reducing condi-
tions. Diazocine does not react with glutathione, indicating intracellular
stability.
Key words bridged azobenzene, diazocine, reductive azo-cyclization,
solvent-free synthesis, oxidative C–C coupling, lead, azoxy, hydrazine,
glutathione
The synthesis of diazocine started with dimerization of
2-nitrotoluene using t-BuOK as a base, and air as the oxidiz-
ing agent. According to our observations, 2,2′-dinitrodiben-
zyl is formed in low yields, even in the absence of additional
oxidizing agents, because part of the nitro compound is sac-
rificed in the oxidation step (and reduced). We therefore
screened the effect of external oxidizing agents on the reac-
tion time, temperature and yields. The yield reported by
Chaudhuri and Ball8 (65%) was increased to 95% by addition
of bromine as the oxidizing agent (Scheme 1). Thereby, the
reaction time was reduced from several hours to 7 minutes.
Diazocines have been known for more than 100 years,
however, it was only recently discovered that they exhibit
extraordinary photophysical and photochemical proper-
ties.1,2 As compared to the most frequently used pho-
toswitch, azobenzene, the parent diazocine has higher
switching efficiencies (100% E→Z, 96% Z→E), and higher
quantum yields (50% E→Z, 72% Z→E). Moreover, diazocines
can be isomerized with visible light (400 nm E→Z, 500 nm
Z→E), and the photodynamics are ultrafast.3 Most impor-
tantly, in contrast to azobenzene, diazocine is more stable
in its sterically demanding Z form than in the slender E con-
figuration. Hence, diazocines are ideal switches in photo-
pharmacology.4,5 Most drugs equipped with an azobenzene
unit are active in their more stable and less hindered E con-
figuration. Biological activity is switched off upon isomeri-
zation with UV light because the bent Z isomer no longer
1. t-BuOK, 0 °C, 2 min
2. Br2, rt, 5 min
abs. THF
95%
NO2 O2N
NO2
Scheme 1 Improved method for the oxidative coupling of 2-nitrotolu-
ene to 2,2′-dinitrodibenzyl
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W. Moormann et al.
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Synthesis
The majority of procedures describing the synthesis of
diazocines are based on the reduction of 2,2′-dinitrodiben-
zyl with Zn and Ba(OH)2, as published by Duval (Scheme
2).1,2,6,9–12 The reported yields vary substantially.
venient method to prepare the diazocine giving the highest
yields. The reaction can be easily monitored by TLC. Diazo-
cine gives rise to a yellow spot which can be switched to a
red color upon irradiation with UV light (and back to yellow
with green light). The colorless hydrazine spot is converted
into the yellow diazocine upon very short exposure to fum-
ing nitric acid vapor, and thus easily identified by subse-
quent switching with UV light. Oxidation of the hydrazine
to diazocine with air and CuCl2 is an almost quantitative re-
action (Scheme 3).
Zn, Ba(OH)2
EtOH/H2O
N
N
NO2 O2N
58%
H
H
Scheme 2 Reduction of 2,2′-dinitrodibenzyl with Zn and Ba(OH)2 as
reported by Duval et al.
CuCl2, O2
According to our observations the process is strongly
dependent on the reaction conditions. We therefore investi-
gated the mechanism in detail by monitoring the interme-
diates and their concentrations during the reduction (Figure
1).
MeOH, 0.1 M NaOH
N
N
N
N
99%
H
H
Scheme 3 Formation of diazocine by oxidation of the corresponding
hydrazine
A reason for the varying yields in previous syntheses
might be the fact that upon standing in air the hydrazine
autoxidizes to the diazocine. By-products during reduction
are the cyclic dimer (16-membered ring) and oligomers.13
Ring-closure reactions are favored over oligomerization
under high dilution conditions, or if performed as heteroge-
neous reactions keeping the local concentration of the reac-
tant low.14,15 Besides reduction with Zn/Ba(OH)2, reactions
with lead under basic conditions (pH 9.5) in methanol and
formic acid as a proton source have been successfully per-
formed.7,10 Under these reaction conditions the cyclic azoxy
compound is formed, which subsequently is reduced with
PCl3 or Ph3P/MoCl2O2(dmf)2. Hence, both procedures re-
ported in the literature are two-step reactions. To avoid
over-reduction to the hydrazine [Zn/Ba(OH)2], or incom-
plete reduction to the azoxy compound (Pb/Et3N/HCOOH),
we investigated the one-step, solvent-free reduction with
lead powder in a ball mill (Scheme 4).16 Avoiding moisture
(dry nitrogen atmosphere), or other additional proton
sources should prevent formation of the hydrazine or di-
amine. Various substituted azobenzenes have been pre-
pared on small scale by Suzuki et al. using this method.17
Figure 1 Fractions of products and intermediates during reduction of
2,2′-dinitrodibenzyl with Zn/Ba(OH)2 as a function of time
Several facts are worth noting. The azoxy compound is
the first isolable reduction product, and it is obviously an
intermediate with a peak concentration of 41% after about 2
hours (16 equiv of Zn powder, 3 equiv Ba(OH)2, ethanol, re-
flux). The azoxy compound is further reduced to the diazo-
cine (peak concentration ~8% after ~3 h) which again is re-
duced to the hydrazine (~58%). Further reduction to the di-
amine is slow (if no further Zn is added). We checked this
mechanistic hypothesis by resubmitting the intermediate
azoxy compound to the same reduction conditions, and ob-
served an analogous concentration dependence of diazo-
cine and hydrazine as shown in Figure 1. The sum of azoxy
compound, diazocine, and hydrazine remains constant
during reduction. There is no loss of material after forma-
tion of the azoxy compound. By-products, such as the di-
mer and higher oligomers, are formed in the first reductive
ring-closure step of the dinitrodibenzyl. We conclude that
reduction to the hydrazine and reoxidation is the most con-
Pb (mesh)
ball mill (50 Hz)
N2, rt, 4 h
NO2 O2N
N
N
51%
Scheme 4 Solvent-free reduction of 2,2′-dinitrodibenzyl with lead
powder in a ball mill
We mixed 2,2′-dinitrodibenzyl with a 10-fold molar ex-
cess of lead powder, and agitated the mixture in a ball mill
under a nitrogen atmosphere. At regular intervals, probes
were taken and analyzed. As in the case of Zn/Ba(OH)2 re-
duction, the cyclic azoxy compound is the first isolable
compound with a peak concentration of 45% after about 2
hours (vibrational frequency 50 Hz). Upon further milling,
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W. Moormann et al.
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the diazocine is formed at the expense of the azoxy com-
pound concentration (Figure 2). The isolated yield of diazo-
cine after 3.5 hours is 51%. No further reduction takes place
after extended periods of milling. The reaction time de-
pends on the scale of the reaction and the milling frequen-
cy.
Figure 3 Switching of diazocine with light of 385 and 530 nm in an
alternating sequence in the presence of glutathione in acetonitrile/water
(1:1) after incubation for 24 h. Absorption at 370 and 500 nm was re-
corded after each switching cycle. No fatigue was observed.
Figure 2 Fractions of products and intermediates during reduction of
2,2′-dinitrodibenzyl with lead powder in a ball mill as a function of time
In conclusion, we optimized the synthesis of parent di-
azocine. The yield of the first step (oxidative dimerization
of 2-nitrotoluene) was improved to 95% by using bromine
as the oxidizing agent (instead of air). The eight-membered
ring in diazocines is rather strained (ring strain ~16 kcal
mol–1). Reductive azo-cyclization of the dinitro precursor,
therefore, competes with cyclic oligomer and polymer for-
mation. Further problems on the reaction pathway to di-
azocine arise from incomplete reduction (azoxy com-
pound), or over-reduction (hydrazine), or further reductive
ring cleavage (diamino compound). We minimized oligo-
mer formation, and avoided over-reduction by performing
the reduction of the dinitro compound under dry and sol-
vent-free conditions with metallic lead in a ball mill. In
contrast to a number of azobenzenes, diazocine is stable to-
wards reduction by glutathione which is an important pre-
requisite for applications in photopharmacology.
The product is separated from the lead powder by ex-
traction with acetone and filtration. Lead should be re-
moved quickly, or protic solvents or moisture should be
carefully avoided. Upon standing of the suspension with
lead under air, further reduction to the hydrazine was ob-
served. Small amounts (~6%) of the dimer (16-membered
ring with both azo groups in E configuration) and higher
cyclic oligomers are formed as well.13
Under physiological conditions, a number of azoben-
zenes (particularly amino-substituted azobenzenes) are re-
duced in vivo to the corresponding anilines, some of which
are carcinogenic.18 Good correlations have been observed
between the glutathione-inducing effect of azo dyes in the
liver and their carcinogenic activities.19 For applications in
photopharmacology, the stability of the switchable drugs
toward reduction by glutathione inside cells is essential.
We therefore subjected diazocine to reduction by gluta-
thione. For solubility reasons, the experiments were per-
formed in a 1:1 acetonitrile/PBS buffer. After incubation of
diazocine for 24 hours, no change in UV–vis absorption was
detected. Furthermore, the diazocine was switched 22
times between the Z and the E configuration with light of
385 and 530 nm in the presence of glutathione. No fatigue,
or side products were detected (Figure 3). Our experiments
indicate that diazocine is stable toward reduction by gluta-
thione. Besides photopharmacology, diazocines have been
proposed as substitutes for azobenzenes in demonstration
experiments, because they can be switched with visible
light and they exhibit a distinct color change.20 The negative
glutathione test gives a first indication that diazocine is
physiologically benign.
Milling reactions were carried out in a 15 mL stainless steel grinding
cup using stainless steel balls of 10 mm diameter in a laboratory ball
milling apparatus (Pulverisette 23, Fritsch GmbH, Idar-Oberstein,
Germany). Test for stability to glutathione reduction: Diazocine was
incubated (24 h, 27 °C) in 1:1 acetonitrile/PBS (1X phosphate-buff-
ered saline:137 mM NaCl, 2 mM KCl, 8 2 mM Na2PHO4, 2 mM KH2PO4,
pH = 7.4) in a 10 mM solution of glutathione. A reaction control was
performed with the use of an Agilent Technologies 1100 Series HPLC
and Agilent Zorbax 5 μm Eclipse XDB-C8, 4.6 × 150 mm column. TLC
plates (Polygram Sil G/UV254 Macherey–Nagel) were used for reac-
tion control. Flash column chromatography was carried out with a
Biotage® Isolera system using Biotage® SNAP ULTRA (HP-Sphere™ 25
μm) columns. Melting points were obtained using a Büchi, Melting
Point M-560 apparatus. IR spectra were recorded with a Perkin–
Elmer 1600 series FT-IR spectrophotometer, using a Golden Gate Dia-
mond ATR unit, A531-G. NMR spectra were recorded using a Bruker
DRX 500 spectrometer [1H NMR (500.1 MHz), 13C NMR (125.8 MHz)]
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–E

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W. Moormann et al.
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Synthesis
without an internal standard. Mass spectra were recorded on a Fin-
nigan MAT 8230 (EI, 70 eV) spectrometer. UV–Vis spectra were re-
corded with a Lambda 14 UV/Vis spectrometer, Perkin–Elmer. Irradi-
ation was performed with LED light sources [385 nm: 12 × Nichia NC-
SU034A, FWHM = 9 nm, P(opt) = 12 × 340 mW, 530 nm: 16 × Luxeon
LXML-PM01-0080, FWHM = 33 nm, P(opt) = 16 × 200 mW], Sahl-
mann Photochemical Solutions.
(Z)-11,12-Dihydrodibenzo[c,g][1,2]diazocine
[CAS Reg. No. 1194317-15-1]
By Reduction/Reoxidation of 2,2′-Dinitrodibenzyl: To a solution of 2,2′-
dinitrodibenzyl (201 mg, 738 μmol) in EtOH (40 mL) were added an
aqueous solution of barium hydroxide [Ba(OH)2·8H2O] (695 mg, 2.20
mmol) in H2O (20 mL) and zinc powder (778 mg, 11.9 mmol), and the
mixture was stirred for 5 h under reflux. The reaction mixture was
filtered through Celite, and the solvent was removed under reduced
pressure. The crude product was dissolved in CH2Cl2 and filtered
through Celite, and the solvent was removed under reduced pressure.
The crude product was dissolved in 0.1 M methanolic NaOH solution
(50 mL), CuCl2 (4 mg, 29.8 μmol) was added, and air was bubbled
through the solution until completion of the reaction. The reaction
was neutralized with 1 M HCl solution. After addition of saturated so-
dium bicarbonate solution, the aqueous layer was extracted with
CH2Cl2. The combined organic layers were dried over MgSO4 and the
solvent was removed under reduced pressure. The crude product was
purified by flash column chromatography (cyclohexane/EtOAc, 3:1,
Rf = 0.51) to afford the product as a yellow solid (89.1 mg, 428 μmol,
58%); mp 103–105 °C.
2,2′-Dinitrodibenzyl
[CAS Reg. No. 16968-19-7]
Under a nitrogen atmosphere, 2-nitrotoluene (2.00 g, 15.0 mmol) was
dissolved in dry THF (90 mL), cooled to 0 °C, followed by addition of
potassium butoxide. The reaction was stirred for 2 min before addi-
tion of bromine (3.12 g, 19.5 mmol). After further stirring for 5 min,
the reaction was added to 500 mL of ice/water. The precipitate was
filtered and the filtrate extracted with CH2Cl2 (3 × 100 mL). The com-
bined organic layers were washed with saturated sodium thiosulfate
solution and saturated sodium chloride solution, then dried over
MgSO4 and concentrated under reduced pressure. The crude product
was purified by crystallization (H2O/EtOH, 1:2) to give 2,2′-dinitro-
dibenzyl as a white solid (1.94 g, 7.13 mmol, 95%); mp 121 °C;
Rf = 0.33 (n-pentane/CH2Cl2, 1:1).
IR (ATR): 3058, 2898, 1813, 1568, 1522, 1480, 1438, 1153, 1083, 1037,
949, 924, 864, 805, 763, 747, 682, 631, 596, 566, 535, 481, 459, 422,
405 cm–1
.
IR (ATR): 2962, 2854, 2343, 1608, 1576, 1509, 1443, 1344, 1310, 1262,
1201, 1164, 1126, 1073, 1041, 959, 859, 787, 749, 704, 666, 567, 531,
1H NMR (500.1 MHz, CDCl3, 300 K): δ = 7.13 (pseudo t, 2 H, H-4), 7.02
(pseudo t, 2 H, H-5), 6.98 (d, J = 7.7 Hz, 2 H, H-6), 6.83 (d, J = 7.8 Hz, 2
H, H-3), 2.87 (mc, 4 H, CH2).
13C NMR (125.8 MHz, CDCl3, 300 K): δ = 155.49, 129.60, 128.08,
127.01, 126.66, 118.70, 31.65.
421 cm–1
.
1H NMR (500.1 MHz, CDCl3, 300 K): δ = 7.96 (dd, J = 8.2 Hz, J = 1.2 Hz,
2 H, H-3), 7.54 (pseudo t, 2 H, H-5), 7.42 (dd, J = 7.7 Hz, J = 1.3 Hz, 2 H,
H-6), 7.38 (pseudo t, 2 H, H-4), 3.25 (s, 4 H, CH2).
13C NMR (125.8 MHz, CDCl3, 300 K): δ = 149.37, 136.01, 133.30,
MS (EI, 70 eV): m/z (%) = 208 (19) [M]+, 179 (100), 165 (61).
132.49, 127.56, 124.84, 34.44.
MS (EI, 70 eV): m/z (%) = 273 (1) [M + H]+, 255 (8), 237 (9), 178 (21),
HRMS (EI, 70 eV): m/z [M]+ calcd for C14H12N2: 208.1001; found:
208.1004.
136 (100), 120 (70), 92 (85).
UV–Vis (MeCN): λmax (log ε) = 401 (2.99), 281 (3.48), 245 (3.96) nm.
By One-Step Reduction of 2,2′-Dinitrodibenzyl with Pb in a Ball Mill:
Under a nitrogen atmosphere, 2,2′-dinitrodibenzyl (320 mg, 1.18
mmol), lead mesh (2.44 g, 11.8 mmol; Alfa Aesar lead powder, 200
mesh, 99.9%), and two stainless steel balls (10 mm diameter) were
added to a stainless steel grinding cup (15 mL). The reaction vessel
was shaken at a rate of 50 Hz for 4 h. The black pasty product was
extracted twice with acetone (200 mL). The extracts were filtered
over Celite and the solvent was evaporated. The crude residue was pu-
rified by flash column chromatography (cyclohexane/EtOAc, 3:1,
Rf = 0.51) to afford the product as a yellow solid (125 mg, 602 μmol,
51%).
5,6,11,12-Tetrahydrodibenzo[c,g][1,2]diazocine (Hydrazine)
[CAS Reg. No. 2225-55-0]
To a solution of 2,2′-dinitrodibenzyl (201 mg, 738 μmol) in EtOH (40
mL) were added an aqueous solution of barium hydroxide
[Ba(OH)2·8H2O] (695 mg, 2.20 mmol) in H2O (20 mL) and zinc powder
(778 mg, 11.9 mmol), and the mixture was stirred for 5 h under re-
flux. The reaction mixture was filtered through Celite and the solvent
was removed under reduced pressure. The crude product was dis-
solved in CH2Cl2, filtered through Celite, and the solvent evaporated.
The residue was purified by flash column chromatography (cyclohex-
ane/EtOAc, 3:1, Rf = 0.72) to afford the product as a colorless solid
(90.0 mg, 429 μmol, 58%); mp 151 °C.
Funding Information
IR (ATR): 3337, 3327, 3049, 2939, 2902, 1606, 1580, 1495, 1454, 1441,
1406, 1234, 1101, 935, 864, 746, 717, 542, 484, 441, 405 cm–1
.
The authors gratefully acknowledge financial support by the Deut-
sche Forschungsgemeinschaft (DFG) within the Sonderforschungs-
1H NMR (500 MHz, acetone-d6, 300 K): δ = 7.03 (d, J = 7.3 Hz, 2 H, H-
6), 6.99 (dt, J = 7.6 Hz, J = 1.5 Hz, 2 H, H-2), 6.83–6.76 (m, 4 H, H-3, H-
5), 6.55 (s, 2 H, N-H), 3.18 (s, 4 H, CH2).
bereich SFB677, ‘Function by Switching’.
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orsch
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n
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e
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en
i
chatf
S(
F
B
6
7
7)
13C NMR (125 MHz, acetone-d6, 300 K): δ = 148.9, 133.8, 131.3, 127.0,
122.0, 117.8, 32.0.
MS (EI, 70 eV): m/z (%) = 210 (100) [M]+.
HRMS (EI, 70 eV): m/z [M]+ calcd for C14H14N2: 210.1157; found:
210.1154.
References
(1) Duval, H. Bull. Soc. Chim. Fr. 1910, 7, 727.
(2) Siewertsen, R.; Neumann, H.; Buchheim-Stehn, B.; Herges, R.;
Näther, C.; Renth, F.; Temps, F. J. Am. Chem. Soc. 2009, 131,
15594.
(3) Siewertsen, R.; Schönborn, J. B.; Hartke, B.; Renth, F.; Temps, F.
Phys. Chem. Chem. Phys. 2011, 13, 1054.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–E

E
W. Moormann et al.
Paper
Synthesis
(4) Lerch, M. M.; Hansen, M. J.; van Dam, G. M.; Szymanski, W.;
Feringa, B. L. Angew. Chem. Int. Ed. 2016, 55, 10978.
(5) Broichhagen, J.; Frank, J. A.; Trauner, D. Acc. Chem. Res. 2015, 48,
1947.
(6) Samanta, S.; Qin, C.; Lough, A. J.; Woolley, G. A. Angew. Chem.
Int. Ed. 2012, 51, 6452.
(7) Eljabu, F.; Dhruval, J.; Yan, H. Bioorg. Med. Chem. Lett. 2015, 25,
5594.
(8) Chauduri, N. K.; Ball, T. J. J. Labelled Compd. Radiopharm. 1980,
18, 1189.
(9) Paudler, W. W.; Zeiler, A. G. J. Org. Chem. 1969, 43, 3237.
(10) Joshi, D. K.; Mitchell, M. J.; Bruce, D.; Lough, A. J.; Yan, H. Tetra-
hedron 2012, 68, 8760.
(11) Tellkamp, T.; Shen, J.; Okamoto, Y.; Herges, R. Eur. J. Org. Chem.
2014, 25, 5456.
(12) Deo, C.; Bogliotti, N.; Métivier, R.; Retailleau, P.; Xie, J. Chem.
Eur. J. 2016, 22, 9092.
(13) Tauer, E.; Machinek, R. Liebigs Ann. Chem. 1996, 1213.
(14) Fan, Q.; Wang, T.; Dai, J.; Kuttner, J.; Hilt, G.; Gottfried, J. M.;
Zhu, J. ACS Nano 2017, 11, 5070.
(15) Bielawski, C. W.; Benitez, D.; Grubbs, R. H. Science 2002, 297,
2041.
(16) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025.
(17) Wada, S.; Urano, M.; Suzuki, H. J. Org. Chem. 2002, 67, 8254.
(18) Mori, H.; Mori, Y.; Sugie, S.; Yoshimi, N.; Takahashi, M.; Hiroaki,
N.-i.; Yamazaki, H.; Toyoshi, K.; Williams, G. M. Cancer Res.
1986, 46, 1654.
(19) Neish, W. J. P.; Davies, H. M.; Reeve, P. M. Biochem. Pharm. 1964,
13, 1291.
(20) Krämer, R. Dissertation; Bergischen Universität Wuppertal:
Germany, 2016.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–E