Organophotocatalytic N-Demethylation of Oxycodone Using Molecular Oxygen

Article abstract of DOI:10.1002/chem.201905505

N-Demethylation of oxycodone is one of the key steps in the synthesis of important opioid antagonists like naloxone or analgesics like nalbuphine. The reaction is typically carried out using stoichiometric amounts of toxic and corrosive reagents. Herein, we present a green and scalable organophotocatalytic procedure that accomplishes the N-demethylation step using molecular oxygen as the terminal oxidant and an organic dye (rose bengal) as an effective photocatalyst. Optimization of the reaction conditions under continuous flow conditions using visible-light irradiation led to an efficient, reliable, and scalable process, producing noroxycodone hydrochloride in high isolated yield and purity after a simple workup.

Full text of DOI:10.1002/chem.201905505

A Journal of
Accepted Article
Title: Organophotocatalytic N-Demethylation of Oxycodone using
Molecular Oxygen
Authors: Yuesu Chen, Gabriel Glotz, David Cantillo, and C. Oliver
Kappe
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To be cited as: Chem. Eur. J. 10.1002/chem.201905505
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Organophotocatalytic N-Demethylation of Oxycodone using
Molecular Oxygen.
Yuesu Chen,[a][b] Gabriel Glotz,[a][b] David Cantillo*[a][b] and C. Oliver Kappe*[a][b]
[a]
Y. Chen, G. Glotz, Dr. D. Cantillo, Prof. Dr. C. O. Kappe
Center for Continuous Flow Synthesis and Processing (CC FLOW),
Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz (Austria),
E-mail: david.cantillo@uni-graz.at; oliver.kappe@uni-graz.at
[b]
Y. Chen, G. Glotz, Dr. D. Cantillo, Prof. Dr. C. O. Kappe
Institute of Chemistry, University of Graz, Heinrichstrasse 28, 8010 Graz (Austria),
E-mail: david.cantillo@uni-graz.at; oliver.kappe@uni-graz.at
Supporting information for this article is given via a link at the end of the document.
Abstract: N-Demethylation of oxycodone is one of the key steps in
synthesis of important opioid antagonists like naloxone or analgesics
like nalbuphine. The reaction is typically carried out using
stoichiometric amounts of toxic and corrosive reagents. Herein we
present a green and scalable organophotocatalytic procedure that
accomplishes the N-demethylation step using molecular oxygen as
the terminal oxidant and an organic dye (rose bengal) as effective
photocatalyst. Optimization of the reaction conditions under
continuous flow conditions using visible-light irradiation led to an
efficient, reliable and scalable process, producing noroxycodone
hydrochloride in high isolated yield and purity after a simple workup.
medicines such as nalbuphine (4c) by varying the alkylating
agent.[11]
There are many methods for the N-demethylation of
alkaloids. Only a few of them are applied for 14-hydroxy
opioids.[12] Traditionally, N-demethylation is accomplished by
refluxing the substrate solution with more than five equivalents
of chloroformate over several hours (Scheme 1B), resulting in
the nor-compounds with moderate to good yields after
hydrolysis.[13] Cyanogen bromide (BrCN) can also demethylate
opioids after protection of the hydroxyl groups (von Braun
reaction).[14] These electrophile-based methods require the use
of extremely corrosive and toxic reagents in large excess,
generating a considerable amount of hazardous waste, limiting
their wider practical use. More recently, several oxidative N-
demethylation methods have been explored.[12] These catalytic
Introduction
reactions typically allow the use of green reagents such as
H2O2
Thebaine (1) is one of the naturally occurring opiate alkaloids.[1]
It is extracted from Papaver bracteatum (Iranian poppy), in
which it can be found in large abundance (up to 26% wt. of dried
latex, 98% wt. of total alkaloids).[2] Thebaine is utilized as
starting material for the synthesis of several drugs. The most
well-known analgesic synthesized from thebaine is oxycodone
(2), which is produced over two synthetic steps (Scheme 1A)
and widely used in clinics to alleviate severe pain caused by
surgeries or cancers.[3] Overdose of opioid analgesics gives rise
to respiratory depression and death.[4] Naloxone (4a), a short-
acting opioid antagonist, has been used for the treatment of
acute poisoning of narcotic opioids since the 1960s.[5] As this
relatively inexpensive medication can completely reverse the
effects of opioid overdose,[6] naloxone is included in the World
Health Organization’s Model List of Essential Medicines.[7]
Naloxone can be prepared from oxymorphone by replacing the
N-methyl by an N-allyl group, with oripavine as the naturally
occurring staring material.[8] However, the natural abundance of
oripavine (up to 1.5 wt% of dried latex of P. orientale, or 27 wt%
of total alkaloids) is much lower than thebaine.[9] Thus, the
synthesis from thebaine via oxycodone 2 is an attractive
alternative (Scheme 1A). In this case the synthetic route also
includes an O-demethylation step with BBr3 at rt.[10] In both
approaches (from thebaine or oripavine), the key intermediates
[15]
and O2[16] as stoichiometric oxidants. In 2008, Hudlicky
and coworkers developed a palladium catalyzed acylative N-
demethylation of morphine-type alkaloids using air or O2 as
oxidant (Scheme 1B).[16-17] Recently, our research group found
that in situ generated palladium nanoparticles (Pd(NP)) can
catalyze the N-demethylation of 14-hydroxy opioids via an 1,3-
oxazolidine intermediate (e.g. 5a) without using acid anhydrides
or O-acyl protection (Scheme 1B).[18] Oxazolidine 5a was
generated via intramolecular nucleophilic addition of the 14-
hydroxy group to the iminium electrophile in intermediate 8a
(Scheme 1B). Its O-protected counterpart 8b was postulated as
intermediate for the N-demethylative acyl migration by Hudlicky
(Scheme 1B)[17]
.
Methods using microreactors for the Pd-catalyzed N-
demethylation of unprotected[18-19] and 3,14-O-protected[20]
oxymorphone (2a) were successively developed, enabling the
reliable and safe preparation of noroxymorphone (3a) on a
kilogram scale.[20] Despite the good isolated yield (~70%) and
high productivity, the O2/Pd(NP) procedure requires a precious
noble metal catalyst and elevated temperatures (120 °C). In this
context, an even more sustainable and economic N-
demethylation procedure for 14-hydroxy-opioids under mild
condition using environmentally friendly solvents and oxidants is
highly desirable.
are the so-called nor-compounds (noroxycodone
3
and
noroxymorphone 3a), which are prepared by the N-
demethylation. Indeed, the following N-functionalization provides
a facile route not only to naloxone, but also to other important
1
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Scheme 1. Significance of N-demethylation in the synthesis of semisynthetic opioids and common methods.
In 2001, Scammells and coworkers reported
a
(Scheme 1B). However, their attempt to demethylate
unprotected oxycodone (2) failed. Based on our experience with
Pd-catalyzed N-demethylations involving iminium intermediates
(8a),[18-20] we postulated that the reaction in principle should be
photochemical N-demethylation method for some polycyclic
alkaloids.[21] The proposed mechanism for the successful
examples involved an iminium ion intermediate (8) generated via
a single electron transfer (SET) – proton transfer (PT)[22] process, feasible, although leading to an oxazolidine product (5) (Scheme
which subsequently decomposed to the secondary amine and
formaldehyde. The authors also observed N-demethylative
acetyl migration of 14-O-acetyl oxycodone (6) catalyzed by
tetraphenylporphyrin (TPP), furnishing N-acetyl noroxycodone
(7) in 34% yield along with an oxidation product after 6 h
irradiation with a 300 W incandescent lamp in an O2 atmosphere
1B). Compared to the O2/Pd N-demethylation method, a
photochemical approach would enable the reaction to be
performed at room temperature using photons as a green
energy source and eliminate the necessity to employ a noble
metal catalyst. Moreover, mass[23] and photon[24] transfer
limitations and safety issues associated with the use of
2
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molecular oxygen in batch reactors[25] could be overcome by
using a continuous flow photochemical setup.
Supporting Information). As expected, the reaction did not
proceed in the absence of light or oxygen (entries 11 and 12).
Eosin Y and RB delivered analogous results. RB was selected
as catalyst for further optimizations due to its higher ISC
efficiency and better solubility in some solvents.
Herein a continuous flow procedure for the photochemical
N-demethylation of oxycodone (2) is presented (Scheme 1B).
The method is based on the generation of an iminium
intermediate (8d) by means of photoredox catalysis using
molecular oxygen as the terminal oxidant. Rose bengal has
been employed as an inexpensive and readily available
photocatalyst. The reaction conditions were optimized and
scaled utilizing a commercial flow photoreactor equipped with
visible light LEDs as the irradiation source. An isolation
procedure was developed to afford noroxycodone hydrochloride
(3·HCl) in good yield and purity (Scheme 1B).
Table 1. Catalyst screening in batch.[a]
LED[
Conv
(%)[c]
Yield 5
entry catalyst (λmax, nm)
Comments
b]
(%)[c]
Results and Discussion
1
2
3
4
TPP (419)
Rh6G (524)
DCA (422)
425
515
425
425
99
40
85
99
57
23
14
11
1. Catalyst Screening and Mechanistic Investigations.
Our study began with a series of batch experiments to establish
the optimal photoredox catalyst and other reaction conditions for
the demethylation reaction (Table 1). LEDs with emission
wavelengths of 425 nm, 455 nm or 515 nm were utilized as light
source. The wavelengths were selected to match the absorption
maxima of the catalysts. In the catalyst screening experiments, a
solution of oxycodone (2) (0.05 M) and catalyst (2 mol%) in DMF
(1.5 mL) was irradiated for 1 h whilst bubbling O2 through the
solution. Then, an aliquot of the reaction mixture was analyzed
by HPLC-UV using an acetic anhydride derivatization method
(see Supporting Information for details).[18] Notably, xanthene
dyes exhibited the best selectivities towards the formation of 5
(entries 7-8). Dyes containing more heavy atoms, i.e., eosin Y
(EY) and rose bengal (RB) provided the highest yields (heavy
atom effect; see Scheme S1 in Supporting Information).
Interestingly, high conversions were achieved by catalysts
featuring high intersystem crossing efficiency (ϕISC), most of
which are also potent singlet oxygen (1O2) sensitizers. Yet, side-
4CzIPN (425)
Ru(bpy)3Cl
5
455
99
43
2 (453)
6
7
EB (517)
EY (520)
RB (549)
RB (549)
RB (549)
RB (549)
RB (549)
515
515
515
515
44
98
99
37
29
78
73
24
28
-
8
9
CBr4 as oxidant[d]
10
11
12
515 CBrCl3 as oxidant[d] 40
515
515
no oxidant[e]
no light[f]
-
-
-
[a] Conditions: 2 (0.05 M) + photocatalyst (2 mol%) in DMF (1.5 mL), O2 (3.0
mLN/min). [b] Irradiation wavelength of the LED utilized. [c] Determined by
calibrated HPLC. [d] 1 equiv and 10 equiv of halogenated oxidant were
evaluated. The reaction mixture was purged with Ar. [e] The solution was
purged with Ar instead of O2 under irradiation. [f] The reaction vial was
wrapped with aluminum foil.
1
products resulting from degradation by O2 were not observed.
Instead, other reactive oxygen species (ROS), in particular
hydrogen peroxide which is formed during the reaction (vide
infra), provoked degradation of the organic compounds. Other
photocatalysis, such as triphenylporphyrin (TPP), 2,4,5,6-
tetra(9H-carbazol-9-yl)isophthalonitrile (4CzIPN), or the typical
Ru(bpy)3Cl2 provided good conversions but poor selectivities
(selectivity refers to the HPLC peak area of the desired product
with respect to the sum of all peaks except the starting material)
(entries 1, 3, 4 and 5). The poor performance observed for the
other photocatalysts could be explained by the electronic
properties of their excited states in some cases. 4CzIPN (entry
4), for example, is a relatively strong oxidant E(3cat*/cat•-) = +
1.35 V (vs SCE),[26] which may account for the low selectivity
obtained. 9,10-Dicyanoanthracene (DCA) (entry 3) exhibits a
large singlet-triplet gap (ΔEST = 1.09 eV)[27] but a very low ISC
efficiency (ϕISC = 0.0085)[28] compared to the xanthene dyes,
which might also point to a reduced selectivity. Remarkably,
when organic halides (CBr4 and BrCCl3)[29] were used as
oxidants instead of O2 (entries 9 and 10), relatively low
conversions were achieved, even after adding 10 equiv of the
halogenated reagents. No improvement was achieved under the
same conditions using Et3N as additive to neutralize the HBr
generated during the reaction (see Figures S18 and S19 in the
Using RB as catalyst, a comparison of the reaction rate at
different temperatures was carried out. For this purpose, the
same batch setup as described for Table 1, equipped with a
transparent water jacket for temperature control, was utilized. A
solution of 2 (0.1 M) and RB (2 mol%) in DMF (1.5 mL) was
irradiated over 35 min whilst bubbling O2 through the solution.
Temperatures ranging from 10 °C to 60 °C were evaluated. The
reaction mixture was monitored by HPLC analysis. As expected,
no significant temperature effects on the reaction rate were
observed, which is common for photocatalytic reactions. The
Stern-Volmer relationship for RB using 2 as quencher resulted in
a curved F0/F vs [2] plot (Figure 1), indicating the existence of
more than one kinetically different quenching site. The data also
suggested a diffusion controlled quench, as less viscous
solvents proved to be more effective (MeOH > EtOH > n-PrOH).
An additional control experiment using the triplet quencher
azulene (10 mol%) as additive inhibited the formation of 5.
These results support the assumption that the electron transfer
takes place with RB in its triplet state (τ = 150 µs), and explain
that catalysts with high ϕISC values exhibited the best
performance.
3
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Figure 1. Stern-Volmer quenching experiment of RB using
2 (OC) as
quencher in different solvents (T = 21 °C, [RB] = 1 μmol·L-1). Viscosity of the
solvents: η (MeOH) = 0.5838 mPa·s, η (EtOH) = 1.170 mPa·s and η (n-PrOH)
= 2.125 mPa·s.
Additional control experiments in deuterated solvents
(CDCl3 and CD3OD) excluded the direct participation of 1O2 in
side-reactions, as no significant changes in the amount of side-
products could be observed (the life time of 1O2 is longer in
deuterated solvents) (see Figure S13 in the Supporting
Information). Yet, photochemically generated ROS were
responsible both for catalyst bleaching and decreased
selectivities. A fast photochemical bleaching of RB could be
observed only in the presence of both O2 and a tertiary amine,
implying the potential formation of ROS during the photocatalytic
cycle (see Figure S15 in Supporting Information). Hydrogen
peroxide is a common ROS encountered in photooxidations.
When H2O2 was added to the reaction mixture as additive,
formation of side products and low product yields were observed
(see Figure S16-17 in Supporting Information). Gratifyingly,
degradation of 5 was determined to be comparatively slow (see
Figure S14). The rate of degradation of 5 was ca. 30 times
slower than its formation under the reaction conditions, thus
explaining the good selectivities achieved. Additionally, these
results also suggested that an immediate quench of H2O2 after
the reaction (before workup) could be essential in order to obtain
high yields, as observed experimentally (vide infra).
Scheme 2. Suggested reaction mechanism.
2. Optimization in Flow.
N-Demethylation of oxycodone (2) has often been carried out in
high boiling polar aprotic solvents such as DMF, DMAc and
DMSO (b.p. > 150 °C).[18-20] To enable a more sustainable
process, in this work we sought for
a greener solvent
alternative.[30] After an extensive solvent screening, a 1:1 mixture
of methanol (MeOH) and n-butyl acetate (n-BuOAc, b.p. =
126 °C) was found to be able to dissolve 2 in a 0.1 M
concentration at 40 °C, and also provided good results for the
demethylation reaction (similar to DMAc or DMF, see Supporting
Information). Our initial flow experiments using a commercially
available flow photoreactor (Corning Lab Photo Reactor)[31] were
carried out using this solvent mixture. The continuous flow setup
(Figure 2a) consisted of two feeds: the solution and oxygen were
introduced with constant flow rates (FL = 0.9 mL/min, FG = 2.1
mLN/min; 1 equiv O2) into the reactor, a glass microreactor plate
(155 × 125 × 8 mm, 2.77 mL internal volume, temperature
40 °C) flanked by two LED panels. The system pressure was
controlled by a back pressure regulator (p = 5 bar) at the outlet.
The substrate solution (0.1 M 2 + 2 mol% RB) was introduced
into the system using a sample loop (10 mL) heated to 50 °C
through a six-way valve. The tubing between the injection loop
and the flow plate was kept short to avoid cooling of the liquid
mixture and potential clogging caused by crystallization of 2.
Based on the experiments described above, an overall
reaction mechanism was formulated (Scheme 2). The reaction
pathway starts with excitation of RB to its singlet state (1RB*),
which is then converted to the triplet state (3RB*). Oxycodone (2)
undergoes an electron transfer with the triplet state of RB. The
resulting radical cation (2•+) is then converted to iminium cation
8d after the hydrogen atom transfer (HAT) with the radical
•-
superoxide anion (O2 ) generated during the catalyst turnover.
Then, 8d undergoes an intramolecular nucleophilic addition to
afford 5 and a stoichiometric amount of H2O2. This mechanism is
in agreement with the typical iminium cation generation
pathways by means of photoredox catalysis.[29]
4
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Figure 2. Flow setup for the N-demethylation of 2 and optimization of the
residence time and relative irradiation power (P/Pmax).
Using green LEDs (λ = 540 nm) at their full power (Pmax
=
18.8 W), we achieved 90% conversion and 71% calibrated
HPLC yield within 2.0 min residence time (tR). A second
processing of the reaction mixture through the reactor under the
same conditions provided 98% conversion of 2 and 82% HPLC
yield of 5 (total residence time tR,tot = 4.0 min). Then, several flow
reactions under variable light irradiation power and residence
time were carried out (Figure 2b). Best yields were achieved
using the maximum power of the light source. Interestingly, an
optimum value for the residence time (ca. 4 min) was clearly
observed. Further prolonging the residence time led to the
partial product decomposition by reaction of 5 with ROS.
Figure 3. Influence of reaction temperature and catalyst loading in the
continuous photochemical generation of 5.
2.3. Oxazolidine (5) Hydrolysis and Product Isolation.
To avoid the requirement of heating the substrate liquid
feed to 50 °C and to ensure that no clogging of the system is
caused by precipitation of 2 in the reactor during prolonged
operation time, the solvent system was further refined. Using a
ternary mixture of MeOH/MeCN/n-BuOAc (1:1:1 vol.), substrate
2 could be dissolved in a 0.1 M concentration at room
temperature (20 °C). With this new solvent, N-demethylation of 2
was performed using a liquid flow rate of 0.5 mLN/min and 6 bar
backpressure. A conversion of 96% and 87% calibrated HPLC
yield of 5 were obtained in a single pass (tR = 3.5 min). Notably,
the reaction temperature did not have a significant influence on
the reaction outcome (Figure 3a), confirming the results already
observed in batch. The catalyst (RB) loading could be reduced
to 1 mol% without adverse effect. Upon further decrease of the
catalyst loading (0.5 mol%), the conversion dropped (Figure 3b).
In contrast, the use of EY as photocatalyst resulted in lower
conversions (< 75%) even when with a catalyst loading of 4
mol% (Figure 3c).
Once the continuous flow photochemical generation of
oxazolidine 5 had been optimized, we turned our attention to the
generation of the target nor-compound 3. The hydrolysis method
developed in our previous research[18] consisted of treating 5
with HCl (1 M, aq.) at 80 °C under reduced pressure (140 mbar)
to enhance the elimination of formaldehyde from the reaction
mixture. However, workup of the reaction mixture obtained after
photolysis experiments at elevated temperatures provoked the
formation of side-products, most probably due to the presence of
ROS (mainly H2O2). For this reason we developed a novel
workup protocol under atmospheric pressure. The crude
photolysis mixture was stirred with 2 equiv of sodium ascorbate
(NaAsc) to quench the ROS and then was refluxed with a 3:1
mixture of 1 M aqueous HCl and ethanol for 2 h. The refluxing
mixture was sparged with argon to facilitate elimination of the
released formaldehyde byproduct. Using the optimized N-
demethylation conditions in combination with this new hydrolysis
procedure, noroxycodone (3) was prepared as its hydrochloride
salt with good purity after an acid-base work-up (Table 2, entries
1-2). The yield of 3 from the larger scale run is slightly higher,
5
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since the operation time at steady state is longer (Table 2, Entry
2). For synthesis on preparative scale (> 1 mmol), the substrate
solution was delivered through the HPLC pump instead of a
sample loop.[32] The stability of the flow system was
demonstrated by a long run over 124 min (6.2 mmol scale) at
20 °C reaction temperature (Table 2, Entry 3). From the
collected reaction mixture, noroxycodone hydrochloride (3·HCl)
was isolated in 68% yield (1.4 g) after hydrolysis.
Experimental Section
Photocatalytic N-Demethylation of Oxycodone (2) and H2O2
quenching. Using the setup shown in Table 2, (reactor settings: FL = 0.5
mLN/min, FG = 2.1 mLN/min, T = 40 °C, p = 6 bar), after warming of the
light source and stabilization of the temperatures and pressure, a 0.1 M
solution of oxycodone (2) and
2 mol% rose bengal (RB) in
MeOH/MeCN/n-BuOAc (1:1:1 vol.) was pumped into the reactor. When
the steady state was reached, the reaction mixture was collected at the
reactor outlet with a graduated cylinder. As soon as the collection was
finished, the volume of the reaction mixture was recorded; the collected
reaction mixture was transferred into a 100 mL three-necked flask and
stirred with 2 equiv sodium ascorbate (NaAsc) over 16 h at room
temperature in the dark.
Table 2. Preparative runs, workup and isolation.[a]
Hydrolysis of Oxazolidine (5) and Isolation of Noroxycodone
Hydrochloride (3·HCl). The reaction mixture after the NaAsc treatment
(H2O2 quenching) was evaporated to dry at 45 °C in vacuo, and then
refluxed with HCl (1 M, aq.)/ethanol (3:1 vol.) for 2 h while argon bubbling.
The hydrolysis mixture was concentrated in vacuo over 10 min at 40 °C,
100 mbar, added with 5 mL HCl (1 M, aq.) and extracted with 2 × 30 mL
CHCl3. The aqueous phase was collected and basified with 25% NH3
solution to pH ≈ 10 and then extracted with 4 × 30 mL CHCl3. The
combined organic phase was dried over anhydrous Na2SO4, filtered and
concentrated in vacuo. The residue was dissolved in 2 equiv HCl (1.25 M,
MeOH solution), evaporated in vacuo to dry, washed with 3 × 2 mL
diethyl ether and dried in vacuo overnight at 40 °C affording
noroxycodone hydrochloride (3·HCl) as water soluble yellowish solid.
Acknowledgements
Scale
Yield 3·HCl
Entry
T (°C)[a]
Purity (%)[c]
(%)[b]
(mmol)
The CC FLOW Project (Austrian Research Promotion Agency
FFG No. 862766) is funded through the Austrian COMET
Program by the Austrian Federal Ministry of Transport,
Innovation and Technology (BMVIT), the Austrian Federal
Ministry of Science, Research and Economy (BMWFW), and by
the State of Styria (Styrian Funding Agency SFG). The authors
gratefully acknowledge Corning SAS for the generous loan of
the Corning Advanced-Flow Lab Photo Reactor used in this
study. We are also thank Prof. Dr. Till Opatz for his informative
suggestions during this research.
1
2
3
1.0
2.2
6.2
40
40
20
70
75
68
94
94
88[d]
[a] Temperature of the photochemical step. [b] Isolated yield. [c] Determined
by HPLC peak area integration. [d] 93% purity obtained after acid-base work-
up (see Supporting Information).
Conclusion
We have developed a photocatalytic procedure for the N-
demethylation of oxycodone (2) using molecular oxygen as the
terminal oxidant and rose bengal as an inexpensive, metal free
organophotocatalyst. Mechanistic studies revealed that
quenching of the triplet state of the catalyst (RB) with 2 plays an
important role in the catalysis. Singlet oxygen does not
contribute to the formation of 5. The ROS generated during the
reaction are responsible for the decomposition of the opiates,
Keywords: photocatalysis • gas/liquid reaction • continuous-flow
• opioid • N-demethylation
[1]
[2]
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Franckh Kosmos Verlag: Stuttgart, 2019.
requiring
a
reductive quench afterwards.
A
scalable
methodology has been achieved by translating the process to a
continuous flow reactor. Under optimal conditions, oxazolidine 5
could be obtained in 87% HPLC yield after a 3.5 min residence
time. Acidic hydrolysis of 5 furnished the desired nor-derivative 3
as its hydrochloride salt with 75% isolated yield. This
photochemical approach avoids the use stoichiometric amounts
of electrophiles, metal catalysts, or harsh reaction conditions
(Scheme 1). In addition, the reaction can be performed under
mild reaction conditions in a relative benign solvent mixture.
[3]
[4]
a) A. O. Gallego, M. G. Baron, E. E. Arranz, Clin. Transl. Oncol. 2007, 9,
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C. Reid, K. Forbes, G. Hanks, Palliat. Med. 2011, 25, 454-470.
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