Electrochemical Scaled-up Synthesis of Cyclic Enecarbamates as Starting Materials for Medicinal Chemistry Relevant Building Bocks

Article abstract of DOI:10.1002/adsc.202000450

The electrochemical Shono oxidation of Boc-protected cyclic amines was revised. The conditions for scalable electrochemical synthesis of cyclic enecarbamates were found. The developed protocol included recycling of the full range of used reagents, favoring to E-factor reduction according to Green Chemistry requirements. The method opened the way for the convenient preparation of previously uncommon materials, which could become useful synthetic intermediates. Their synthetic potential was evaluated in [2+1] and [2+2] cycloadditions as well as electrophilic functionalization. Moreover, functionalized enecarbamates with carbonyl groups in β-position were used as latent 1,3-bielectrophiles in classical heterocyclizations. In a case of the hydrazine, the corresponding unusually decorated pyrazoles were prepared. The proposed methodology is a straightforward tool for the design and synthesis of Medicinal Chemistry relevant building blocks. As examples, 5-fluoro pipecolic and 3-fluoro isonipecotic acids were synthesized starting from Boc-protected esters of the pipecolic and the isonipecotic acids respectively; the 5-step approach to pyrazole containing α-aminoacids with different linkers between the aminoacidic and pyrazole moieties was elaborated based on the cheapest commercially available racemic and chiral cyclic α-aminoacids; the convenient approach to the functionalized tetrahydropyrido[3,4-d]pyridazines was proposed starting from Boc-protected ester of the isonipecotic acids. (Figure presented.).

Full text of DOI:10.1002/adsc.202000450

Title: Electrochemical scaled-up synthesis of cyclic encarbamates as
starting materials for Medicinal Chemistry relevant building blocks
Authors: Oleksandr Tereshchenko, Maryana Perebiynis, Irina Knysh,
Olesia Vasylets, Anna Sorochenko, Eugeniy Slobodyanyuk,
Eduard Rusanov, Oleksandr Borysov, Sergey Kolotilov,
Sergey Ryabukhin, and Dmitriy Volochnyuk
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000450
Link to VoR: https://doi.org/10.1002/adsc.202000450

10.1002/adsc.202000450
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Electrochemical Scaled-up Synthesis of Cyclic Enecarbamates
as Starting Materials for Medicinal Chemistry Relevant
Building Bocks
Oleksandr D. Tereshchenko,a Maryana Y. Perebiynis,a Irina V. Knysh,a Olesia V.
Vasylets,a Anna A. Sorochenko,a Eugeniy Yu. Slobodyanyuk,a,b Eduard B. Rusanov,b
Oleksandr V. Borysov,a,b Sergey V. Kolotilov,c Sergey V. Ryabukhin,a,d* Dmitriy M.
Volochnyuka,b,d*
a
Enamine Ltd, 78 Chervonotkatska str., Kyiv, Ukraine
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanska str., Kyiv, Ukraine
L. V. Pisarzhevskii Institute of Physical Chemistry, National Academy of Sciences of Ukraine, 31 Nauki ave., Kyiv,
b
c
Ukraine
d
Taras Shevchenko National University of Kyiv, 60 Volodymyrska str., Kyiv, Ukraine
E-mail: s.v.ryabukhin@gmail.com. Phone: +380506424763; mail: d.volochnyuk@gmail.com. Phone: +380967139494.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. The electrochemical Shono oxidation of Boc- Medicinal Chemistry relevant building blocks. As examples,
protected cyclic amines was revised. The conditions for 5-fluoro pipecolic and 3-fluoro isonipecotic acids were
scalable electrochemical synthesis of cyclic enecarbamates synthesized starting from Boc-protected esters of the
were found. The developed protocol included recycling of the pipecolic and the isonipecotic acids respectively; the 5-step
full range of used reagents, favoring to E-factor reduction approach to pyrazole containing α-aminoacids with different
according to Green Chemistry requirements. The method linkers between the aminoacidic and pyrazole moieties was
opened the way for the convenient preparation of previously elaborated based on the cheapest commercially available
uncommon materials, which could become useful synthetic racemic and chiral cyclic α-aminoacids; the convenient
intermediates. Their synthetic potential was evaluated in approach to the functionalized tetrahydropyrido[3,4-
[2+1] and [2+2] cycloadditions as well as electrophilic d]pyridazines was proposed starting from Boc-protected
functionalization. Moreover, functionalized enecarbamates ester of the isonipecotic acids.
with carbonyl groups in β-position were used as latent 1,3-
bielectrophiles in classical heterocyclizations. In a case of the
hydrazine, the corresponding unusually decorated pyrazoles
Keywords: Electrochemistry; Green Chemistry; Cyclic
enecarbamates; Shono oxidation; Scale up;
Cyclopropanation; Recyclization; Medicinal chemistry;
Building blocks
were prepared. The proposed methodology is
a
straightforward tool for the design and synthesis of
reactions did not allow to achieve the desired
complexity of new drugs,[7] which were more close to
the natural compounds.[8] Usually, the complexity and
novelty of the compound libraries come from the
building blocks, which now become more diverse and
sophisticated.[9] Access to diverse and unique BB
collections has a tremendous impact on the speed and
scope of different Medicinal Chemistry projects.[10]
Taking into account the speed and cost-effectiveness
of BB delivery,[11] producers of new BB prefer to use
synthetic sequences based on the reliable
transformations and easy accessible cheap starting
materials. Therefore, effective, but not optimized or
adapted for multigram scale synthesis, new
approaches do not attract the attention of BB producers,
even if they lead to unique Medicinal Chemistry
Introduction
Modern organic synthesis and drug discovery strongly
influence each other.[1] Innovation in synthetic
chemistry allows successful solving problems in all
phases of drug discovery,[2] on the other hand, the
medicinal chemistry poses more and more complex
challenges to synthesis.[3] Moreover, the challenges
contradict each other. Current Medicinal Chemistry
needs access to new chemical space, especially based
on new and unusual scaffolds.[4] However, in spite of
newly appeared approaches,[5] medicinal chemists
prefer to use a limited number of well-known robust
procedures in their synthetic planning, especially in
parallel (library) synthesis.[6] The comparable analysis
showed, that the combination of the above-mentioned
1
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10.1002/adsc.202000450
Advanced Synthesis & Catalysis
relevant chemotypes. These new chemotypes begin to
be actively used only after the innovative development
of the multigram synthesis of the key intermediates.
The bright example of such recent chemical
difficulties overcoming is the development of key
intermediates synthesis for the straightforward
installation of the saturated bioisosteres of benzene.[12]
Nevertheless, there are many original novel structural
motifs, which still need cost and time optimization for
active use. As a part of our ongoing efforts on the
adaptation of existing and developing of new effective
approaches to the advanced building blocks for
medicinal chemistry,[13] we turned our attention to the
chemistry of cyclic enecarbamates I. These
compounds are known from 1969[14] and find
application in academician investigations as starting
materials for natural products and bioactive molecules
synthesis in mg scales.[15] Some representative
examples of compounds made from cyclic
enecarbamates are shown on Figure 1.
The methodology developed had an impact on the
availability of cyclic enecarbamates and, therefore, on
the investigation of their properties. It was
demonstrated on the compound Ia as an example.[17]
The reported approach was used in our company for
the synthesis of Medicinal Chemistry relevant
trifluoromethyl
substituted
3‐
18
]
azabicyclo[n.1.0]alkanes.[ In this research specific
behavior of five-membered lactams in the LiBEt3H
reduction step was detected. The scale up procedure
didn't work on cyclic lactams other than 5-membered
ones. The same results were obtained independently
by other researchers. When the above-mention
protocol was used for cyclic lactams containing more
than 5 atoms in the ring significantly lower yields were
19
20
]
]
obtained.[
Meanwhile, the Reaxys database[
analysis showed that significant applicability was
found only for two cyclic enecarbamates Ia and Ic
from the representative set. Moreover, very interesting
boc-3,4-dihydro-morpholine If is still unknown.
21
Previously only corresponding Cbz-derivative[ ] and,
by analogy, 3,4-dihydro-2H-1,4-oxazine-3-carboxylic
acid derivatives[22] were synthesized through
cyclization in mg scales. The E-molecules[23] search
showed that only 3 compounds were commercially
available from reliable suppliers and only the parent
compound Ia was available in up to 100 g quantity.
However, the price of Ia does not allow to generate a
cost-effective design of Medicinal Chemistry relevant
building blocks on its base (Figure 3).
Figure 1. Examples of natural products and bioactive
compounds obtained from cyclic enecarbamates I.
In order to expand our initial stock in a cost-
effective way by multigram quantities of diverse cyclic
enecarbamates for the further design and synthesis of
Medicinal Chemistry relevant building blocks, we
started to search for a new approach to these
compounds. We have chosen an approach based on
organic electrochemistry, which becomes popular
The industrial application of cyclic enecarbamates
chemistry started from the anti-diabetic drug
Saxagliptin which was co-developed in 2007 by
Bristol-Myers Squibb and AstraZeneca. The synthesis
of the drug was based on cyclopropanation chemistry
of the key intermediate I. In a course of the project the
preparative approach to cyclic enecarbamates was
elaborated based on one-pot conversion of the lactam
carbamates type II to target products by reduction with
LiBEt3H, and in situ dehydration with TFA-DIPEA
(Figure 2).[16] The approach was scaled up to 100 kg of
key intermediates Ia,b. But the development of eco-
friendly protocols is still needed.
24
]
either in industrial or laboratory scales.[
Results and Discussion
In our previous project directed to the synthesis of 3-
oxadiazolyl/triazolyl morpholines, we successfully
25
used modified Shono oxidation[ of Boc-protected
morpholine 1a to corresponding 3-methoxy derivative
2a on 40g scale.[26] The products of the Shono
oxidation were close structural analogues of
compounds of type 3 and also could be converted to
]
27
]
desired enecarbamates by methanol elimination.[
Therefore, we decided to investigate the Boc-
morpholine electrochemical oxidation more deeply in
order to obtain still unknown compound 3a
(Scheme 1).[28]
Figure 2. One-pot conversion of lactam carbamates to
cyclic enecarbamates.
2
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10.1002/adsc.202000450
Advanced Synthesis & Catalysis
Figure 3. Reaxys and E-molecules data for representative cyclic enecarbamates.
Key points for the optimization were taken from our
previous experience and literature data.[25] As the first
estimation of whether the reported procedure could be
applied to electrochemical oxidation of new Boc-
protected amines, electrochemical properties of Boc-
protected morpholine (1a) were evaluated by cyclic
voltammetry (CV) and compared with the reported CV
curves for Boc-protected pyrrolidine.[29] MeCN was
chosen as a solvent in order to see the potentials of the
first steps of compounds oxidation with minimal
influence of possible subsequent reactions; the
evolution of CV curves upon addition of MeOH was
also studied (see SI for details).
Thus, it can be concluded from the CV measurements
that oxidation of 1 occurred at E at the level of 2.40 V
and GC surface is not passivated in the course of the
process. The behavior of 1 was quite similar to the
properties of previously reported Boc-protected
pyrrolidine,[29b] and in view of this similarity, we used
the electrolysis conditions reported in [25] as the first
step in search of optimized conditions for electrolysis
of 1.
The first attempts to carry out preparative
electrolysis of 1a were performed at constant current
using tetraethylammonium tosylate as the background
electrolyte; different combinations of the electrodes
The oxidation of 1 in MeCN solution on GC
electrode started at 1.81 V, and the shoulder on CV
curve was found at E = 2.40 V with Bu4NBF4
(TBATBF) as the supporting electrolyte; hereinafter
all potentials are given vs. Ag/AgCl (the CV curve is
presented on Figure 4 and details are provided in the
SI). This process could be associated with one- or two-
electron oxidation of 1, leading to the formation of
radical cation or cationic enecarbamate.[29a] The
current values at this potential almost did not change
upon the repeated scans, it can be concluded that there
was no noticeable adsorption of the reaction products
on the electrode. Also, these current values were
proportional to the concentration of 1, indicating that
the process was controlled by Randles–Ševćik law.[29a]
The addition of methanol (in the concentration range
between 0.01 M and 0.4 M) to 0.01 M solution of 1 did
not cause a change of the peak current, indicating that
reaction of the oxidized species with methanol was not
the rate-limiting stage of the electrochemical oxidation.
Figure 4. CV curves for 1 in MeCN solution on GC
electrode at three different concentrations; the supporting
electrolyte - Bu4NBF4.
3
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10.1002/adsc.202000450
Advanced Synthesis & Catalysis
A
A
A
A
V
V
V
V
Scheme 1. Optimization of Shono oxidation protocol for the Boc-morpholine 1 as a model substrate.
were tested (boxes 1 and 2 on Scheme 1). After
consumption of 3.6 F/mole of electricity in both
experiments, high conversion values and good yields
of the target product were obtained. In theory, 2 F/mol
is required for Shono oxidation.[29a] However, a higher
quantity of electricity is used for this process (4
F/mole)[29a], which can be partially consumed for
methanol oxidation. Both GC and carbon electrodes
appeared to be suitable for electrochemical synthesis
of enecarbamate 3a (Scheme 1).
In this study, we did not intend to perform a
systematic examination of the influence of the reaction
conditions on the conversion of 1a, since the aim was
just to develop a multi-gram protocol for the
enecarbamate preparation. So, in order to minimize
efforts, further experiments were directed on testing
some ideas, based on comparison with literature data
or reasonable assumptions.
The aim of the second step was to check if
tetraethylammonium tosylate could be replaced by
tetraethylammonium perchlorate, because preparative
electrochemical oxidative methoxylation of a similar
compound, N,N-diethylbenzamide at the presence of
perchlorate (Bu4NClO4) was much more efficient
compared to a similar process in a solution of tosylate
(EtN4OTs).[29a] Being aware of success, we used
Et4NClO4 and also changed the electrodes: Pt mesh
was used as anode while GC plate was used as cathode
(box 3 on Scheme 1). Surprisingly, this attempt failed,
no reaction occurred. To check if the reaction was
possible in these conditions (Pt electrode and
Et4NClO4 as supporting electrolyte), we repeated the
experiment with an increased quantity of electricity
reaction time (4.0 F/mol instead of 3.6 F/mol, (box 4
on Scheme 1). In this case, Pt mesh was changed by Pt
plate: the idea was to minimize by-products formation,
but again this idea was not fruitful, and the reaction
4
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10.1002/adsc.202000450
Advanced Synthesis & Catalysis
ended up with the formation of di-methoxy-Boc-
morpholine 4a in a near 70% yield. The structure of 4a
was proven by single-crystal X-ray structure
determination. Production of this species could be
considered as consequent two-step 4-electron
oxidation of Boc-protected morpholine; the second
oxidation step can be occurred due to the increase of
methoxy-Boc-morpholine concentration in course of
the process as well as due to continuous growth of the
process potential in galvanostatic mode. The second
reason seemed to be more probable, because the
formation of 4a was not observed in the cases of
previous experiments (boxes 1 and 2), where the
reaction mixture after a certain time contained a high
concentration of "semi-oxidation intermediate" 3a, but
no product of further oxidation could be detected.
On the results of the previous experiment (box 4 on
Scheme 1) in order to control oxidation potential
electrochemical oxidation of 1 was carried out in
potentiostatic mode (box 5 on Scheme 1) at constant
potential 1.9 V using the same Pt electrodes and the
same Et4NClO4 as the supporting electrolyte. In order
to minimize the formation of 4a the potential was
tetrafluoroborate electrolyte was expected to occur at
slightly higher potential.[29c] The reaction time was 1.5
times increased. As a result, we got more than 80%
conversion of 1 and good selectivity with respect to
formation of the desired compound 3a. Unexpectedly,
it was found the MeOH elimination from 2a during the
evaporation of the solution giving the crude desired
carbamate 3a was very efficient compared to the
previous experiment. This effect was attributed to the
catalytic action of TBATBF, and this feature was taken
into account in the selection of conditions for multi-
gram electrolysis.
Finally, we decided to check if lithium perchlorate
(box 8 on Scheme 1) could be used instead of
tetraethylammonium salts (boxes 3, 5 and 6 on Scheme
1), because LiClO4 was successfully used several
times in Shono oxidation processes.[30] Electrolysis of
1 in potentiostatic mode at 2.1 V in LiClO4 solution
(the same potential as in box 6 with Et4NClO4) led to
the formation of di-methoxy-Boc-morpholine 4a in 48
h. Thus, LiClO4 appeared to be suitable however in a
quick test we did not find any advantage over Et4NBF4.
Notably, in the experiments described above, we did
chosen at the level close to the lowest acceptable value, not find any preference for a certain type of the
estimated from CV experiments, as described above,
taking into account that (1) oxidation of the previously
reported N-Boc-proline methyl ester in MeOH
occurred at a lower potential than in MeCN, see SI for
details, and (2) it was recently shown that irreversible
oxidation of organic compounds in tetrafluoroborate
electrolyte occurred at a slightly higher potential than
in perchlorate electrolyte.[29c] An additional reason for
the use of lower potential was the minimization of
possible methanol oxidation (the methanol oxidation
onset was ca. 2.3 V in 0.4 M solution in MeCN, see SI
for details). However, in pure methanol, the oxidation
apparently starts at lower potential. The conversion of
1 in these experiments was less than 60% and the
selectivity with respect to compound 3a was good. In
order to increase the conversion, an attempt to raise the
potential to 2.1 V was performed (box 6 on Scheme 1),
but it did not cause significant improvement. Notably,
on the grounds of the experiments shown in boxes 4-6
(Scheme 1), Et4NClO4 could be considered as a
suitable supporting electrolyte, because the desired
enecarbamate formed. However, our expectations of
very high yields in perchlorate solutions were
overestimated.
electrodes, since the reaction proceeded (and high
conversions were achieved) on all types of the
electrodes tested.
Among the tested conditions the cases, shown in
boxes 1, 2 and 7, were the most promising for target
enecarbamate 3a formation. For multi-gram scale
electrolysis galvanostatic mode was chosen because
control of constant current was simpler than control of
constant potential. TBATBF was chosen, first of all,
due to its catalytic effect in the transformation of 2a to
3a. Using in-house made electrochemical cell with 7
graphite rod electrodes (150 mm, d = 12 mm, see
pictures on scheme 2) the transformation of ca. 0.5 kg
of Boc-protected morpholine 1 was performed in 2.3 L
MeOH under constant 7.5 A current with 50 g of
TBATBF as the supporting electrolyte leading to the
solution containing ca. 87% of pure compound 2. The
reaction course was additionally monitored by TLC.
Thereby, 87 % yield was achieved at the consumption
of 3.1 F/mol of electricity, 14 % less than in small-
scale experiments described above. We can note that a
scale-up of the synthesis resulted in lower electricity
consumption. The obtained solution was evaporated at
70 °C. The isolation/purification procedures included
distillation with further flash chromatography
purification affording target compound 3 in 85%
preparative yield (Scheme 2). The purified compound
3 according to the described procedure possessed good
stability and could be kept at normal conditions for 1
year without decomposition. These data indicate that
the compound 3a becomes attractive advanced
intermediate due to cost-effective synthesis and good
storage ability. Moreover, it should be noted, that all
In addition, a significant disadvantage of Et4NClO4
was its potential explosivity. Tetraborofluoride salts
seemed to be a suitable safe alternative.[29d] On the next
step (box 7 on Scheme 1) we decided to perform
electrolysis in potentiostatic mode at potential 2.2 V
using TBATBF and the same electrodes as in box 3
(Scheme 1). The potential was slightly increased
compared to the previous experiments (box 6 on
Scheme 1) because, as mentioned above, oxidation in
5
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10.1002/adsc.202000450
Advanced Synthesis & Catalysis
reagents and solvents were recovered by distillation
and TBATBF was recovered by simple crystallization
from EtOAc. The developed method can be considered
as more ecofriendly compared to previously reported
for enecarbamates type 3a.
The developed protocol was tested on other Boc-
protected cyclic amines, which could lead to cyclic
carbamates not accessible in the multigram scale by
LiBEt3H/TFA - DIPEA protocol. The electrochemical
behavior of the compounds 1d (as a racemic mixture
or as pure enantiomers R or S), 1e, and 1f, evaluated
by CV, was quite similar to the properties of 1a. In the
case of all these compounds irreversible oxidation
occurred at potentials slightly higher than in the case
of 1a (2.6, 2.6 and 2.45 V, respectively, compared to
2.4 V for 1a, see SI for details). In the case of 1f, some
signs of electrode passivation were found which can
be caused by adsorption of the reaction products.
For the preparative electrolysis of these compounds,
the same conditions were chosen as for 1a. Since the
electrolysis was carried out in galvanostatic mode, no
A
Scheme 2. Optimized conditions and machinery for multigram scale Shono oxidation with further obtaining of encarbamate
3a.
corrections associated with higher oxidation potentials
were made. The results of the tests are shown on
Scheme 3. Among 6- and 7-membered substrates all
gave high preparative yields on more than 100 g scale
except thiomorpholine. In the latter case, the sulfur
oxidation was the major process instead of the
expected enecarbamate formation. It should be noted
that cyclic amides considered in this study did not tend
to undergo dealkylation, which can occur in the case
of non-cyclic analogues.[24d-f] In cases of piperidine-
based compounds, the preparative yield on the
methanol elimination step was higher when the crude
product after methanol evaporation was additionally
heated at 100 °C in toluene at the presence of NH4Br
(such treatment was not required in the case of other
compounds reported herein, since they underwent
demethoxylation at the presence of TBATBF, vide
supra). Similarly to Boc-3,4-dihydro-morpholine 3, all
obtained cyclic carbamates exhibited excellent storage
ability. Thus, it can be concluded that the
electrochemical Shono oxidation of Boc-protected
cyclic amines followed by methanol elimination is the
best method for the cyclic enecarbamates production
for further commercialization.
It should be noted that all methoxy-derivatives type
2 reported herein can be isolated using a slightly
modified
procedure,
see
SI for
details.
Electrochemical methoxylation of all α-substituted
Boc-dialkylamines 1, studied in this work, resulted in
6
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10.1002/adsc.202000450
Advanced Synthesis & Catalysis
A
Scheme 3. The scope of the multigtam Shono oxidation/elimination protocol.
Scheme 4. [2+1] cycloadditions of N-Boc-3,4-dihydro-morpholine 3a.
the formation of cis-isomers in respect of R and OMe
substituents position to the heterocyclic ring, as it
could be concluded by NMR analysis of all
compounds and X-ray structures of two
representatives, 2d and 4a.
deprotection of these compounds by treatment with
HCl in MeOH led to final amines 5a(cis) and
5a(trans). The structure of 5a(cis) was confirmed by
X-ray single crystal analysis (Scheme 4). The
compound
3a
was
also
subjected
to
All abovementioned carbamates obtained in
multigram quantities by described protocol become
available and attractive starting materials for the
design and synthesis of Medicinal Chemistry relevant
building blocks based thereon. Firstly, the most
interesting Boc-3,4-dihydro-morpholine 3 was tested
in our in-house program directed to the synthesis of
innovative fluorine-containing building blocks,
particularly in [2+1] cycloaddition reactions with
difluorocyclopropanation by Me3SiCF3 – NaI system
in THF,[13c] affording corresponding fused
difluorocyclopropane 6a. Deprotection of 6a by TFA
led to TFA salt of amine 7a, which possessed
increased stability in comparison with non-oxygenated
analogues.[31] The compound could be stored at –
10 °C for several months (Scheme 4).
The compound 3a also was tested in [2+2]
cycloadditions with ketenes, used in our in-house
building block programs,[32] their reactions with non-
oxygenated cyclic enecarbamates were described.[33]
In a case of compound 3a, bearing donors from both
sides of double bonds, the reaction with 2-methylprop-
1-en-1-one generated from isobutyryl chloride/Et3N
fluorine-containing
carbenes/carbenoids.
The
compound 3 was subjected to CuCl-mediated
trifluoromethyl cyclopropanation with CF3CHN2.[18]
The reaction afforded the mixture of Boc-protected
diastereomers 4a(cis) and 4a(trans) in ca. 4 : 1 ratio;
7
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10.1002/adsc.202000450
Advanced Synthesis & Catalysis
was not regioselective. Moreover, fragmentation of the
fused cyclobutanone products upon chromatographic
separation occurred evidencing for its instability in
such conditions.
The electrophilic substitution reactions were tested
for compound 3a. The direction of such reactions was
unclear because 3a was the compound bearing both
enecarbamate and vinyl ether functions. In classical
reactions of electrophilic substitution, such as
trifluoroacyclation by TFAA and Vilsmeier–Haack
formylation, compound 3a behaved as enecarbamate
giving compounds 8a and 9a, respectively. The
regiochemistry of the products was unambiguously
solved by X-ray diffraction study of the compound 9a.
Both these reactions were scaled up to 100 g giving
functionalized derivatives in good preparative yield
(Scheme 5). The trifluoroacyclation by TFAA and
Vilsmeier–Haack formylation of other enecarbamates
3b-d, f proceeded smoothly giving the corresponding
products 8b-d, f and 9b-d, f in good preparative yields
on 30-50 g scale (Scheme 6), similarly to the
abovementioned 3a.
Scheme 5. Electrophilic substitution in N-Boc-3,4-dihydro-
morpholine 3a.
In a course of this project, the new method for
preparation of Br-containing enecarbamates was
developed based on the bromination of cyclic
enecarbamates 3b-f (Scheme 6). Previously
electrochemical bromination of such carbamates in
MeOH was proposed by Shono leading to β-
brominated enecarbamates 11 through addition
product type 12.[34] It was also reported that addition
products type 12 could be prepared by enecarbamate
treatment with NBS in MeOH.[15d] However, this
approach could not be applied for preparation of the
Scheme 6. Electrophilic substitution in cyclic encarbamates.
Br-containing enecarbamate 11, because basic
treatment of the addition product type 12 led to
the β-brominated enecarbamates 11 on 100 g scale
from one synthetic run.
27
bromine elimination.[ We optimized and scaled up
the one-pot synthesis of β-brominated enecarbamates
11 for more than 100 g in excellent preparative yield.
The protocol included carbamate treatment by Br2 in
DCM leading to its addition to double bond giving 10
followed by elimination of one bromine at the
presence of TEA. The approach allowed us to obtain
]
In the frame of this project, we also tried to develop
a preparative method for the introduction of iodine to
β-position of the corresponding Boc-dialkylamines
leading to the compounds type 13 (Scheme 6). These
compounds are valuable synthetic intermediates.
Previously they were prepared by iododecarboxylation
in a small scale.[35] In our case, we tested the sequence
8
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10.1002/adsc.202000450
Advanced Synthesis & Catalysis
of enecarbamate iodination in methanol followed by
removal of the methoxy group by Et3SiH - BF3∙Et2O
system.[15d] The latter two-step sequence appeared to
be preparative on 5 g scale from starting compound 3b,
however, the yield was 38%.
crystal X-ray diffraction analysis of 15d and 16f
derivatives. This approach was scaled up to 30 g of
both compounds, which are fluorinated analogues of
important for Medicinal Chemistry pipecolic and
isonipecotic acids (Scheme 7). It should be noted that
the 5-fluoropipecolic acid was previously synthesized
in our company starting from trans-N-benzyl-2,5-
dicarbomethoxy pyrrolidine and it was based on
morph-DAST mediated rearrangement leading to ring
expansion. However, the rearrangement product was
minor,[36] therefore, this acid was not used in our
Medicinal Chemistry program.
In spite of low yields of MeO-group reductive
removal in iodo derivatives type 12b, we decided to
use a similar approach for the fluorine atom
introduction into the cycle. The treatment of
encearbamates 3d and 3f bearing ester function by
Selectfluor in MeOH led to addition products 14d and
14f, respectively, as the mixtures of hardly separable
diastereomers (Scheme 7). Further reduction of the
fluorinated products by Et3SiH - BF3∙Et2O led to
orthogonally protected (N-Boc, CO2Me) fluorinated
aminoacids 15d and 15f as diastereomeric mixtures. In
the case of 15d trans-isomer was dominating, while in
the case of 15f the mixture contained cis-isomer as the
major component. These diastereomers were easily
separated from the minor isomers by column
chromatography. The configurations of both major
isomers were unambiguously determined by single-
The next milestone in the study was the utilization
of formylated and trifluoroacylated encarbamates as
latent
bielectrophilic
synthons
for
heterocyclization.[37] The simplest hydrazine hydrate
was chosen as model binucleophlic reagent for
recyclization. Firstly, we chose heterocyclization
protocols described earlier for 4-trifluoroacetyl-2,3-
dihydropyrroles bearing CO2Me group at the nitrogen
atom and applied such protocol to the Boc-protected
compounds 8 and 9.[38] In our case, the abovementi-
Scheme 7. Synthesis of 5-fluoro pipecolic and 3-fluoro isonipecotic acids.
oned methods worked, but the yields of the desired
products were low. It could be explained by the lower
activity of the latent cyclic electrophilic center due to
the significant steric hindrance of the Boc group in
comparison with the CO2Me one. As a consequence,
transacetylation of hydrazine hydrate by Boc occurred.
In order to improve the yield, the special Boc-
deprotection procedure was elaborated for the
compounds 8 and 9 by KOH in water at rt by analogy
with alkaline Boc-deprotection of N-protected
aromatic heterocycles.[39] In the case of functionalized
encarbamates bearing ester function 8d, 8f, 9d, and 9f
the Boc deprotection was accomplished by hydrolysis
of the esters. Further treatment of the deprotected
compounds 17 and 18 by NH2NH2·2HCl in dioxane
lead to clean recyclization to pyrazoles 19 and 20
respectively. The structures of the compounds 19a and
19b (as hydrochlorides) were confirmed by single
crystal X-ray analysis. In the case of substrates type 17
and 18 bearing CO2H functions the reactions provided
corresponding amino acids 19d,f and 20f (Scheme 8).
This approach was easily scaled up to 100 g in the case
of all above-mentioned pyrazoles. Notably, for
functionalized
Boc-3,4-dihydro-morpholine
3
previously not reported pyrazoles linked with
OCH2CH2 group at the 4th position were obtained,
which are of high interest for Medicinal Chemistry.
But in the case of chiral substrates obtained from both
enantiomers of enecarbamate 3d this approach
dramatically failed due to full racemization.
9
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000450
Advanced Synthesis & Catalysis
Scheme 8. Recyclization reaction of functionalized carbamates 8, 9 to pyrazoles 19, 20.
Scheme 9. Behavior difference of the compounds 8f and 9f in the reaction with binucleophiles.
Therefore, for these substrates, the alternative
recyclization protocol was developed, this new
protocol was based on slow acidic Boc-deprotection
during the reaction. It was found that reflux with
hydrazine dihydrochloride in 10% solution of HCl in
water-dioxane during 20 h were the best conditions.
Using such conditions both enantiomers of pyrazolyl-
containing aminoacids 19d were synthesized in 80%
(for S) and 83% (for R) yields on 10 g scale
respectively (Scheme 8). The efficacy of elaborated
approach was also demonstrated by the synthesis of
the aminoacid 19e(S) from the well-known,
commercially available 5-membered enecarbamate –
(R)-1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrole-
2-carboxylic acid (see SI).
Scheme 9. In the case of Boc-deprotected derivative
with carboxylic function at the 4th position, only push-
pull enaminone fragment was able to react with the
nucleophiles due to the high reactivity of the enamine
function in comparison with the non-electrophilic
carboxylic group. In the case of NH2NH2 such
reactivity pattern was proven by exclusive formation
of the pyrazole derivative 19f and 20f (see scheme 8).
Vice versa, in the case of Boc-protected ester
derivatives 8f and 9f, the cyclic electrophilic center is
“blocked” by sterically hindered Boc-group while the
ester function was electrophilic. Therefore, we
.
expected that the reaction with NH2NH2 H2O had to
lead to tetrahydropyrido[3,4-d]pyridazin-1(2H)-one
derivatives.
Taking in mind that Boc-group at the nitrogen atom
blocked the nucleophilic attack in reactions of 8 and 9,
were decided to try redirection of the regioselectivity
in the heterocyclization reaction with binucleophiles in
a case of isonipecotic acids derivatives 8f and 9f. The
representative illustration of this idea is shown on
Indeed, isonipecotic acid derivatives 8f and 9f
reacted with 3 eq of NH2NH2∙H2O in i-PrOH under
reflux selectively affording tetrahydropyrido[3,4-
d]pyridazin-1(2H)-ones 21f and 22f, which
crystallized from the reaction mixture upon cooling
(Scheme 10). These reactions were easily scaled up to
10
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10.1002/adsc.202000450
Advanced Synthesis & Catalysis
60 g and the products became good starting materials
for the design of the tetrahydropyrido[3,4-
d]pyridazine libraries with several diversity points. It
should be noted, that tetrahydropyrido[3,4-
sequence of steps included photochemical chlorination
with autoclave pyridine hydrogenation over freshly
prepared PtO2, which limited the scale of the synthesis
of key parent compound 22f to 5 g from 1 synthetic
run.
d]pyridazin-1(2H)-one
building
blocks
were
developed by us earlier [40], but the previously reported
Scheme 10. The synthesis of building blocks based on tetrahydropyrido[3,4-d]pyridazine scaffold starting from isonipecotic
acid derivatives 8f and 9f.
Therefore, the method proposed by us earlier did not
allow the wide use of the above-mentioned building
block in our Medicinal Chemistry programs. The Boc
protected compounds 21f and 22f could be easily
alkylated at N2-position giving (after deprotection)
blocks type 23f and 24f bearing N6 amino function.
This sequence opened the door for the
protected cyclic amines leading to the synthesis of
corresponding carbamates could be optimized and
scaled up to 0.5 kg from 1 synthetic run. This
improvement opens the door to the active use of these
compounds as starting materials possessing excellent
storage ability for the design and synthesis of
Medicinal Chemistry relevant building blocks on its
base. This opportunity was previously not available
(except five-membered encarbamates) because of the
limited accessibility of these compounds in gram scale.
Notably, the developed protocol complies with the
current Green Chemistry requirements.
tetrahydropyrido[3,4-d]pyridazin-1(2H)-one
based
libraries via parallel synthesis with diversity points at
N2 and N6 positions. Alternatively, change of the Boc-
protection to more stable CO2Me the reaction with
POCl3,
allowed
to
obtain
1-chloro
tetrahydropyrido[3,4-d]pyridazines 31f and 32f, which
were the key BB for the tetrahydropyrido[3,4-
d]pyridazine based libraries with diversity points at C1
and N6 positions via nucleophilic substitution at
C1/deprotection/nitrogen functionalization at N6.
However, when we tried to prepare the parent C1-
unsubstituted compound via reductive dechlorination
of 31f with H2 over Pd/C, we found that the
hydrogenation at 40 atm led to the product of quite
selective partial reduction of pyrazine ring 33f - new
Fsp3-rich scaffold. Its structure was proven by single
crystal X-ray diffraction study.
The parent N-Boc-3,4-dihydro-morpholine was
synthesized for the first time and its chemical
properties were tested in [2+1], [2+2] cycloadditions
as well as electrophilic substitutions. The novel,
unique building blocks based on 2-oxa-5-
azabicyclo[4.1.0]heptane framework as well as
functionalized N-Boc-3,4-dihydromorpholines were
obtained. In the case of encarbamates, derived from
Boc-protected esters of pipecolic and isonipecotic
acids, the stereoselective (trans-, in the case of
pipecolic acid, and cis-, in the case isonipecotic acid)
introduction of the fluorine atom in the 5th and the 3rd
position, respectively, was developed based on
electrophilic fluorination by Selectfluor with
subsequent MeO-group reductive removal by Et3SiH.
All obtained cyclic encarbamates were subjected into
Vilsmeier–Haack formylation and trifluoroacyclation
affording latent 1,3-bielectrophilic compounds, which
Conclusion
As a result of this study, we showed that the well-
known electrochemical Shono oxidation of Boc-
11
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000450
Advanced Synthesis & Catalysis
(50.0 g, 0.15 mol) were dissolved in dry MeOH (2400 mL)
and the solution obtained was placed into a 3L undivided
cell with a cooling mantle equipped with seven graphite rod
electrodes (150 mm, d 12mm, see pictures). The mixture
was cooled down to 15 °C and then electrolyzed under a
constant current 7.5A (initial potential was raised from 17V
to 21V progressively). After 3.1 F/mol, the mixture was
concentrated in vacuum and heated for 3 hours at 70 °C
under reduced pressure (100 mm Hg) in a rotary evaporator.
The reaction course was additionally monitored by TLC.
Then the mixture was extracted twice with EtOAc (500 mL).
EtOAc layer washed twice with 200 mL of water, dried over
Na2SO4 and concentrated under reduced pressure, distilled
at 1 mm, collected fraction 60-65 ºC, The desired product
were investigated in classical heterocyclization with
hydrazine. Thus, the method for preparation of the
corresponding pyrazoles, decorated by unusual
manner including chiral examples, was developed. In
the case of enecarbamate derived from Boc-protected
ester of isonipecotic acids, the efficient synthetic route
to tetrahydropyrido[3,4-d]pyridazine derivatives was
elaborated.
The developed procedures are simple, cheap and
time-effective. Therefore, the reaction sequences
developed in this investigation were involved into
REAL building block program[41] and building blocks
synthesized were input into REAL database
program[42]. This investigation meets the criteria of
“translational chemistry” proposed by P. Baran[43] and
means almost immediately introduction the results into
market as building blocks, advanced synthetic
intermediates as well as using the innovative protocol
developed in P@D projects without significant
optimization.
was
purified
by
flash
chromatography
in
“interchem”PuriFlash® (in
a
gradient from ratio
CHCl3/MeCN 1:0 to 0:1). The enecarbamate 3a was
obtained as a colourless liquid (435.0 g, 85% yield).
Procedure
B.
Synthesis
of
(1R*,6S*,7R*)-7-
(trifluoromethyl)-2-oxa-5-azabicyclo[4.1.0]heptane
5a(trans) and (1R*,6S*,7S*)-7-(trifluoromethyl)-2-oxa-
5-azabicyclo[4.1.0]heptane 5a(cis). CF3CHN2 (5 eq;
obtained as described in ref 18) was gradually blown off by
an inert gas from the generator flask and passed through a
drying tube (MgSO4) into a vessel containing a stirring
mixture of 3a (18.5 g, 0.1 mol) and anhydrous CuCl (0.5 g,
5 mmol) in CH2Cl2 (300 mL). The reaction was monitored
by 1H NMR spectroscopy. After the starting material had
disappeared, trifluoromethyldiazomethane bubbling was
immediately stopped. The reaction mixture was filtered off
and concentrated in vacuo. The oily residue was purified by
flash column chromatography with a hexane/EtOAc
mixture (4:1) as an eluent to afford isomer 4a(trans)
(Rf~0.5) as a yellow oil in 53% yield (14.2 g) and 4a(cis)
(Rf~0.35) as a light yellow solid in 15% yield (4.0 g,
m.p.=73-75 ºC). The separated isomers were dissolved in
saturated HCl solution in dioxane[44] and stirred overnight at
rt. The reaction mixture was evaporated and the residue was
triturated with a mixture of MTBE/MeCN (4/1). The
precipitates formed were filtered off and dried. The desired
products obtained in 94% (5a(trans), 10.1 g, beige powder,
m.p. = 111-113 ºC) and 96% (5a(cis), 2.9 g, beige powder,
m.p. 116-118 ºC) yields respectively as hydrochlorides.
Experimental Section
General information. The solvents were purified
according to the standard procedures. All starting materials
were obtained from Enamine Ltd. Melting points were
1
measured on automated melting point system. H, 13C, and
19F NMR spectra were recorded on a Bruker 170 Avance
500 spectrometer (at 500 MHz for Protons and 126 MHz for
Carbon-13) and Varian Unity Plus 400 spectrometer (at
400 MHz for protons, 101 MHz for Carbon-13, and
376 MHz for Fluorine-19). Tetramethylsilane (1H, 13C) or
C6F6 (19F) were used as standards. Elemental analyses were
performed at the Laboratory of Organic Analysis, Institute
of Organic Chemistry, National Academy of Sciences of
Ukraine, their results were found to be in good agreement
(±0.4%) with the calculated values. Preparative HPLC
analyses were done on an Agilent 1200. Mass spectra were
recorded on Agilent 1100 LCMSD SL instrument (chemical
ionization (APCI)). Preparative chromatography was
performed on “interchem”PuriFlash® machine. CCDC-
1982686 (2d), CCDC-1982687 (4a), CCDC-1982688
(5a(cis)), CCDC-1982689 (9a), CCDC-1982690 (15d(sr)),
CCDC-1982691 (16f(sr)), CCDC-1982693 (19a), CCDC-
1982694 (19b), CCDC-1982692 (33f) contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Procedure C. Synthesis of 7,7-difluoro-2-oxa-5-
azabicyclo[4.1.0]heptane 7a.[13c] Sodium iodide (3.0 g,
0.02 mol) was added to a solution of 3a (18.5 g, 0.1 mol) in
anhydrous THF (200 mL) under an argon atmosphere and
heated to reflux. Trimethyl(trifluoromethyl)silane (57.0 g,
0.4 mol) was added dropwise for 8 hours. The reaction
mixture was heated overnight. Then, the additional
trimethyl(trifluoromethyl)silane (28.5 g, 0.2 mol) was
added, and the reaction mixture was refluxed for an
additional 24 hours. When the conversion was complete, the
solvent was evaporated, and the crude product was distilled
under reduced pressure. The product was formed and
purified by flash column chromatography hexane/EtOAc
9:1. The compound 6a was obtained in 86% yield (20.2 g).
The obtained product was dissolved in TFA and heated at
60 ºC for an hour. The precipitates formed was filtered off
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
Detailed experimental procedure for the synthesis of all
compounds as well as its characterization is available in the
supporting information. The representative examples of
general protocols are given below.
Procedure A. Typical protocol for cyclic enecarbamates
synthesis from Boc-protected cyclic amines N-Boc-3,4-
dihydro-morpholine 3a. N-boc morpholine (512.0 g,
2.73 mmol) and tetrabutylammonium tetrafluoroborate
12
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10.1002/adsc.202000450
Advanced Synthesis & Catalysis
and dried. The desired product 7a obtained in 91% yield as
trifluoroacetate (22.6 g).
Procedure G. Typical protocol for the formation of 3-iodo-
2-methoxy derivatives. (2S*,3R*)-tert-butyl 3-iodo-2-
methoxypiperidine-1-carboxylate 12b. The encarbamate
3b (18.5 g, 0.1 mol) was dissolved in 400 mL of 0.5M
solution of NaOMe in MeOH. Then the solution of I2 (25.5
g, 0.1 mol) in DCM 400 mL was added dropwise to the
stirring reaction mixture at rt for a 1 hour. Then the mixture
was stirred at rt for an additional half an hour. After that, the
20% solution of Na2SO3 in water (500 mL) was added. The
mixture obtained was stirred for 5 minutes and then,
extracted with DCM 2x500 mL. The organic layer was
separated and dried under Na2SO4, the solvent was removed
under reduced pressure and the crude product was formed.
The residue was solved in hexane (400 mL) and placed to a
freezer at -20 ºC for 24 hours. The precipitate formed was
filtered off, washed with hexane 3x50mL and dried. The
iodide 12b was obtained in 63% yield (21.5 g). The iodide
obtained was dissolved in DCM (200 mL), and mixed with
Procedure D. Typical protocol for trifluoroacylation of
cyclic
enecarbamates.
Tert-butyl
5-(2,2,2-
trifluoroacetyl)-3,4-dihydropyridine-1(2H)-carboxylate
8b. The corresponding encarbamate 3b (92.0 g, 0.5 mol)
was dissolved in 800 mL of DCM and dry pyridine (47.5 g,
0.6 mol) was added. The solution obtained was cooled down
to 10 ºC and then TFA (63.0 g, 0.55 mol) was added
dropwise at 10-15 ºC for 1 hour and then left for 16 hours at
rt. After that, the reaction mixture poured into a cold 5%
solution of NaHCO3 and the desired product extracted
2x300 mL of DCM, washed with water 200 mL, then 20%
water solution of citric acid 2x200 mL, and water again
500 mL. The organic layer was dried under Na2SO4. The
solvent was removed under reduced pressure. The crude
product formed with 90% purity. The desired product was
.
in BF3 Et2O (9 g, 0.07 mol). The reaction mixture was
purified
by
flash
chromatography
in
cooled to -90 ºC and Et3SiH was added dropwise under this
temperature. After that the reaction mixture was warmed up
to rt. The solvent was removed under reduced pressure and
the crude product was formed. The desired product was
“interchem”PuriFlash® (in
hexane/MTBE 9:1 to 0:1). The final compound 8b (113.1 g,
81% yield) was obtained as a yellow crystalline powder.
a
gradient from ratio
purified
“interchem”PuriFlash® (in
CHCl3/MeCN 1:0 to 0:1). The desired iodide 13b was
obtained in 38% yield (7.1 g).
by
flash
chromatography
gradient from ratio
in
Procedure E. Typical protocol for Vilsmeier–Haack
formylation of cyclic enecarbamates. Tert-butyl 6-formyl-
2H-1,4-oxazine-4(3H)-carboxylate 9a. A solution of dry
DMF (110 g, 1.5 mol) in 540 mL of DCM was placed into
a three-neck round flask equipped with a mechanic stirrer
and and POCl3 (184 g, 1.2 mol) was added dropwise at 5-
15 ºC. After that, the reaction mixture stands by for 10 min
and 500 mL of methylene was added, the mixture was
cooled down to 0 ºC and solution of morpholine
encarbamate 3a (219.0 g, 1.01 mol) in 200 mL of DCM was
added dropwise at 0 ºC. Afterward, the reaction mixture was
stood for 1 hour at 10 ºC and 2 hours at rt. The solution was
poured into 3 kg of ice with 7.2 mol of 1M KOH, extracted
3x200 mL of DCM, washed with brine and dried under
anhydrous Na2SO4. The desired product was purified by
flash chromatography in “interchem”PuriFlash® (in a
gradient from ratio CHCl3/MeCN 1:0 to 0:1). Aldehyde 9a
was isolated as beige powder (122.8 g, 57% yield, m.p. =
130ºC).
a
Procedure H. Typical protocol for the formation of 3-
fluoro-2-methoxy derivatives. (2S*,5R*,6S*)-1-tert-butyl
2-methyl
5-fluoro-6-methoxypiperidine-1,2-
dicarboxylate 14d. The enecarbamate 3d (24.1 g, 0.1 mol)
was dissolved in 100 mL CH3CN/MeOH (ratio 2:1) and
Selectfluor (39.0 g, 0.11 mol) was added. After the reaction
mixture was stirred at rt for 14 hours. After the reaction
completed (monitored by TLC), the solvent was removed by
evaporation. 300 mL of water was added and the desired
product was extracted with ethyl acetate (3x100 mL).
Combined organic layers were dried over MgSO4 and
evaporated. The product was purified by flash column
chromatography with a hexane/EtOAc (9:1) mixture as
eluent. The desired fluoride 14d was obtained in 74% yield
(21.6 g). as a mixture of diastereomers. The products also
can be used in the next step without further purification.
Procedure F. Typical protocol for the formation of 3-
bromoenecarbamates. 1-tert-butyl 2-methyl 5-bromo-3,4-
dihydropyridine-1,2(2H)-dicarboxylate 11d.[45] The
encarbamate 3d (96 g, 0.3 mol) was dissolved in 800 mL of
DCM and Br2 (50 g, 0.31 mol) was added dropwise at
–50-60 ºC. After that, the reaction mixture was stirred for
15 min with further dropwise addition of TEA (61 g, 0.6
mol) at –50-60 ºC. The bath was removed and the reaction
mixture was stirred for 2 h. Then, the reaction mixture was
poured into a cold 5% solution of Na2S2O3, washed with
water (500 mL) and the organic layer was dried under
Na2SO4, the solvent was removed under reduced pressure
and the crude product was formed with 86% purity. The
desired product was purified by flash chromatography in
Procedure I. Typical protocol for the formation of 3-fluoro
derivatives.
(2S,5R)-methyl
5-fluoropiperidine-2-
carboxylate 16d(srs). The compound 14d (29.1 g, 0.1 mol)
was dissolved in 200 mL of DCM and triethylsilane (19.8 g,
0.17 mol) was added. Then the reaction mixture was cooled
to 0 ºC and TFA (114.0 g, 1.0 mol) was added dropwise to
the stirring reaction mixture at 0 ºC for 2 hours. After, the
mixture was warmed up to rt and stirred at rt for 48 hours.
The solvent was removed at 40 ºC and MeOH (200 mL),
TEA (50.6 g, 0.5 mol) and BOC-anhydride (32.7 g, 0.15
mol) were added to the residue. The obtained reaction
mixture was stirred overnight, and MeOH was evaporated.
The product was formed and purified by flash
chromatography in “interchem”PuriFlash® (in a gradient
from ratio CHCl3/MeCN 1:0 to 0:1). The compound
15d(srs) was obtained in 58% yield (15.2 g). The product
was dissolved in saturated solution of acidic dioxane at rt.
“interchem”PuriFlash® (in
a
gradient from ratio
CHCl3/MeCN 1:0 to 0:1). The desired bromide 11d was
obtained in 84% yield (80.7 g).
13
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000450
Advanced Synthesis & Catalysis
The precipitate formed as hydrochloride was filtered off,
washed by ether (2x50 mL) and dried. The product 16d(srs)
was obtained in 92% yield (13.9 g) as a white powder.
d]pyridazin-1(2H)-one 27f. Piridazinone 21f (64 g,
0.2 mol) was suspended in EtOH (400 mL) and 3 eq of 31%
water solution of HCl was added. Then the reaction mixture
was refluxed for an hour. After that, EtOH was removed
under reduced pressure. The desired product 27f was
crystallized from CH3CN and obtained as a yellow powder
in 97% yield (49.6 g, m.p. = 176 ºC) as hydrochloride.
Procedure J. Typical protocol for the recyclization of
trifluoroacetyl and formyl derivatives to pyrazoles. 2-((3-
(trifluoromethyl)-1H-pyrazol-4-yl)oxy)ethanamine 19a.
Compound 8a (140.6 g, 0.5 mol) was dissolved in MeOH
(1 L) and the solution of KOH (42.0 g) in 200 mL of water
was added. The reaction mixture was stirred for 48 hours at
rt. After that, MeOH was removed under reduced pressure
and water was acidified with citric acid and stood by for
1.5 hours. The precipitate formed was filtered off, washed
with water (2x100 mL) and dried in exicator under P2O5.
The product 17a was obtained as a yellowish solid in 86%
yield (78.0 g, m.p. = 205-208 ºC). Compound 17a can be
used in the next step without additional purification. The
product 17a (72.0 g, 0.4 mol) was dissolved in EtOH 1 L in
Erlenmeyer flask, then the reaction mixture was refluxed
with hydrazine hydrate (60.0 g, 1.2 mol) for 4 hours. After
that, the solvent was removed under reduced pressure,
extracted with methylene-water to remove the excess of
hydrazine. The organic layer was evaporated and 3 eq of
31% water solution of HCl was added. Then the solvent was
removed under reduced pressure again. The desired amine
19a was crystallized from CH3CN and obtained as the
hydrochloride in 88% yield (81.5 g) as a yellow powder.
Procedure N. Synthesis of compounds 25f and 26f. 2-
methyl-4-(trifluoromethyl)-5,6,7,8-
tetrahydropyrido[3,4-d]pyridazin-1(2H)-one
25f.
Piridazinone 21f (64.0 g, 0.2 mol) was dissolved in DMF
(200 mL). Then NaH (5 g, 0.21 mol) was added and MeI
(28.4 g, 0.2 mol) was added dropwise for an hour. The
reaction mixture was stirred overnight. After that 20 mL of
water was added and the solvent was removed under
reduced pressure. Hexane (200 mL) was added to the
residue. The suspension was stirred and the hexane was
decanted from the precipitate. Then the residue was
dissolved in EtOAc (500 mL) and washed by water 2x200.
The organic layer combined and the solvent was removed
under reduced pressure. The crude product was treated with
MTBE, and then was crystallized from MTBE and washed
by the mixture MTBE/hexane 1:1. The corresponding
product 23f was obtained as a white powder in 40% yield
(26.7 g). The BOC-deprotection was performed the same as
described in procedure M. The desired product 25f was
obtained as a beige powder in 94% yield (20.3 g) as
hydrochloride.
Procedure K. Synthesis of optically pure S and R 2-amino-
4-(3-(trifluoromethyl)-1H-pyrazol-4-yl)butanoic acids
19d(S) and 19d(R). The product 8d (R or S isomer)
(134.9 g, 0.4 mol) was dissolved in DXN (500 mL) in the
three-neck round flask equipped with a mechanic stirrer.
After that, hydrazine dihydrochloride (47.0 g, 0.4 mol) and
10% water solution of HCl (0.5 L) were added. The reaction
mixture was stirred for 16 hours at 70 ºC. The solvent was
removed under reduced pressure. The corresponding amine
19d was crystallized from CH3CN and obtained as the
hydrochloride in 83% yield (78.7 g) with 95% ee (m.p. =
210-212 °C). 0.1% FA-ACN 30-40% ACN 7 min. Zorbax
Eclipse-plus C18 4.6*100 mm, 3.5 mkm with Marfey's
Reagent EE 95.3%.
Procedure O. Synthesis of compounds 31f and 32f. Methyl
1-chloro-4-(trifluoromethyl)-7,8-dihydropyrido[3,4-
d]pyridazine-6(5H)-carboxylate 31f. Piridazinone 27f
(51.0 g, 0.2 mol) was dissolved in CH3CN:H2O mixture (1:1,
1 L) and KOH (18.0 g, 0.45 mol) was added. The reaction
mixture was cooled to 5 ºC and methyl chloroformate (21 g,
0.22 mol) was added dropwise to the stirring solution during
1 h. Then the solvent was removed under reduced pressure
and water (500 mL) was added to the residue. The desired
product was extracted from the suspension obtained by
DCM (3x200 mL). The organic layer combined and the
solvent was removed under reduced pressure. The
corresponding product 29f was crystallized from EtOAc and
obtained as a white powder in 68% yield (37.7 g).
Compound 29f (27.7 g, 0.1 mol) was mixed with POCl3
(92 g, 0.6 mol) in the three-neck round flask equipped with
a mechanic stirrer. The reaction mixture was stirred for 3
hours at 80 ºC. The excess of POCl3 was removed in vacuo
and caramel-like syrup was obtained. This residue was
poured into 3 kg of ice with of 25% water solution of NH3
(10 mol), extracted 3x300 mL of DCM, washed with brine
and dried under anhydrous K2CO3. The organic layer
combined and the solvent was removed under reduced
pressure. The residue was dissolved in 300 mL of DCM and
flashed through 6 cm of the silica gel pad. The solvent was
removed again. The product 31f was obtained as a yellowish
solid in 92% yield (54.4 g, m.p. = 121 ºC).
Typical protocols for the synthesis of tetrahydropyrido[3,4-
d]pyridazines
Procedure L. Synthesis of compounds 21f and 22f. tert-
butyl
1-oxo-4-(trifluoromethyl)-1,2,7,8-
tetrahydropyrido[3,4-d]pyridazine-6(5H)-carboxylate
21f. Compound 8f (168.7 g, 0.5 mol) was dissolved in
i-PrOH (1,5 L) in Erlenmeyer flask equipped with a
condenser and hydrazine hydrate (40 g, 0.8 mol) was added.
Then the reaction mixture was refluxed for 4 hours. After
that, i-PrOH was removed under reduced pressure and the
residue was diluted by water 500 mL and extracted by DCM
3x200 mL. The organic layer was separated and the solvent
was removed in vacuo. The desired product 21f was
crystallized from EtOAc and obtained as a white powder in
88% yield (140.5 g).
Procedure P. Synthesis of 33f. Methyl 4-
(trifluoromethyl)-1,4a,5,7,8,8a-hexahydropyrido[3,4-
d]pyridazine-6(2H)-carboxylate 33f. 31f (5.0 g,
0.017 mol) was dissolved in 60 mL of MeOH in 100 mL
Procedure M. Synthesis of compounds 27f and 28f. 4-
(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-
14
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10.1002/adsc.202000450
Advanced Synthesis & Catalysis
autoclave, 2 g of 10% Pd(C) was added. The mixture was
blow off with hydrogen to scavenge air and autoclave was
closed. The reduction of 31f was performed with TEA
(1.89 g, 0,019 mol) under 40 atm and 40 ºC for 6 h. The
mixture was filtered off, the solution was evaporated, the
residue was diluted by water 100 mL and extracted by DCM
2x30 mL. The solvent was evaporated under reduced
pressure. The desired product was recrystallized from
MTBE and obtained as a beige powder in 45% yield (3.18 g,
m.p. = 137 ºC).
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Acknowledgements
The work was supported by Enamine Ltd. The authors thank
Prof. Andrey A. Tolmachev for his encouragement and support
and Dr. Halyna Buvailo for their help with manuscript preparation.
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FULL PAPER
Electrochemical Scaled-up Synthesis of Cyclic
Enecarbamates as Starting Materials for Medicinal
Chemistry Relevant Building Blocks
A
Adv. Synth. Catal. Year, Volume, Page – Page
Oleksandr D. Tereshchenko, Maryana Y.
Perebiynis, Irina V. Knysh, Olesia V. Vasylets,
Anna A. Sorochenko, Eugeniy Yu. Slobodyanyuk,
Eduard B. Rusanov, Oleksandr V. Borysov, Sergey
V. Kolotilov, Sergey V. Ryabukhin,* Dmitriy M.
Volochnyuk*
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