Diastereoselective synthesis of CF3-oxazinoquinolines in water

Article abstract of DOI:10.1039/c9gc03044a

A highly efficient stereoselective synthesis of CF₃-oxazinoquinolines was elaborated using the reaction of CF₃-ynones with quinolines in water. It was demonstrated that under these green conditions, the reaction proceeds up to 20 times faster to provide target compounds in almost quantitative yields. Moreover, this method is devoid of any chromatographic purification to give CF₃-oxazinoquinolines with complete diastereoselectivity. The presented eco-friendly approach was found much more efficient than standard reactions in organic solvents. The synthetic utility of the prepared CF₃-oxazinoquinolines was demonstrated.

Full text of DOI:10.1039/c9gc03044a

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Diastereoselective synthesis of
CF3-oxazinoquinolines in water†
Cite this: Green Chem., 2019, 21,
6353
Vasiliy M. Muzalevskiy, a Kseniya V. Belyaeva,b Boris A. Trofimov *b and
a
Valentine G. Nenajdenko
*
A highly efficient stereoselective synthesis of CF3-oxazinoquinolines was elaborated using the reaction of
CF3-ynones with quinolines in water. It was demonstrated that under these green conditions, the reaction
proceeds up to 20 times faster to provide target compounds in almost quantitative yields. Moreover,
this method is devoid of any chromatographic purification to give CF3-oxazinoquinolines with complete
diastereoselectivity. The presented eco-friendly approach was found much more efficient than
standard reactions in organic solvents. The synthetic utility of the prepared CF3-oxazinoquinolines was
demonstrated.
Received 29th August 2019,
Accepted 14th October 2019
DOI: 10.1039/c9gc03044a
rsc.li/greenchem
fungicidal.16,17 Modulation18 and activities of AMPA receptors
Introduction
against Alzheimer’s and type 2 diabetes disease19 were also
Organofluorine chemistry is one of the rapidly expanding documented. A number of 1,3-oxazine motif-based drugs were
areas of organic chemistry,1 defining its current shape. approved by the FDA and have been already marketed.
Fluorinated molecules possess unique physicochemical and Efavirenz (Stocrin® and Sustiva®),20,21 dolutegravir (Tivicay®
biological properties, which allow organofluorine compounds approved in 2013)22 and bictegravir (Biktarvy® approved in
to be intensively exploited as construction materials, com- 2018)23 are used for the treatment of patients with HIV.
ponents of liquid crystalline compositions, agrochemicals and Etifoxine (Stresam®) is anxiolytic and an anticonvulsant
pharmaceuticals.2 According to some estimations, about drug,24 which potentiates the GABAA (γ-aminobutyric acid)
20–25% of currently used drugs3 and agrochemicals4 contain receptor function.25,26 Dirithromycin (Dynabac®) is a macro-
at least one fluorine atom. Heterocycles are also attractive lide glycopeptide antibiotic, which is used for the treatment of
structural elements for medicinal chemistry owing to their many different types of bacterial infections, such as bronchitis,
various biological activities. Indeed, numerous drugs and agro- pneumonia, tonsillitis, and even skin infections.27 The new
chemicals are heterocyclic compounds.5 About 59% of small- drug mirvetuximab soravtansine now is in Phase III clinical
molecule drugs, approved by the US FDA, contain a nitrogen trial for the treatment of platinum-resistant ovarian cancer
heterocycle in their structure.6 As a result, the search for novel (Fig. 1).28
effective methodologies for the synthesis of fluorinated hetero-
Another trend of modern organic chemistry is so-called “on
water” synthesis.29 The definition of this class of reactions can
cycles has been an important task in recent decades.7
The attention paid to the compounds bearing a 1,3-oxazine be rationalized following the attributes formulated by
moiety and their fused analogs has been growing in recent Sharpless and co-workers: (a) when insoluble reactant(s) are
years8,9 due to their wide range of biological activities, stirred in aqueous emulsions or suspensions without the
making them prospective targets for drug design.10 Molecules addition of any organic cosolvents, (b) a considerable rate
with a 1,3-oxazine framework exhibited various types of acceleration is often observed in reactions carried out under
activities such as anticoagulant,11 analgesic,12 antispasmo- these conditions over those in organic solvents.30 Such reac-
dic,12 antidepressant,13 tuberculostatic,14,15 antibacterial and tions have a number of benefits in terms of environmental
impact, effectiveness, cost of goods and simplicity of the reac-
tion protocol. Water is a cheap, safe, non-toxic, and environ-
aM. V. Lomonosov Moscow State University, Department of Chemistry,
Leninskie Gory 1, Moscow, 119991, Russian Federation.
mentally friendly solvent, as well as an indispensable medium
for all living organisms. Organic compounds are often in-
soluble in water, so that reaction products can be precipitated
or separated as an incompatible layer from the aqueous
medium after the reaction. The reaction products can be easily
isolated by simple filtration, saving work up time, solvents,
E-mail: nenajdenko@org.chem.msu.ru
bA. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of
Sciences, 1 Favorsky Str., Irkutsk, 664033, Russian Federation. Fax: +(395-2)41-93-46
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9gc03044a
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Fig. 1 1,3-Oxazine motif-based drugs.
silica gel, etc. Hence, a significant fraction of the synthetic tive solvent in view of its non-toxicity and safety for both
organic community had focused on the search for novel “on environment and human health. One can assume that water is
water” reactions.31 Here, we report an expedient diastereo- not suitable as a solvent for this reaction because both
selective “on water” synthesis of CF3-oxazinoquinolines from reagents are only poorly soluble in water. Nevertheless, we
quinolines and CF3CO-acetylenes.
attempted to perform a reaction of model ketone 2a with qui-
noline 1a in water. As expected, being added to a vial with
water, ketone 2a (1 equiv.) and quinoline (0.95 equiv.) formed
a liquid phase at the bottom of the vial. Surprisingly, after
stirring for several minutes, the liquid phase started to solidify
Results and discussion
α,β-Unsaturated CF3-ketones have attracted a lot of attention as and became completely solid in about 30–40 minutes
building blocks for the synthesis of fluorinated heterocyclic (Scheme 1).
compounds of various structural motifs.32 Investigating the
The NMR analysis of the reaction mixture after 1 h reveals
synthetic scope of CF3-ynones for heterocyclizations, we have full consumption of quinoline. Thus, compared to the reaction
elaborated novel approaches for the preparation of fluorinated in MeCN, the reaction in water proceeds at least 20 times
derivatives of diazepines,33 pyrimidines,34 thiophenes,35 tri- faster. This fact can be easily explained by taking into account
azoles,36 pyrazoles37 and oxazinoquinolines.38 Recently, we the higher concentration of reagents under these conditions.
have reported a three-component reaction between azines, In fact, we believe that the reaction leads to the formation of
CF3-ynones and water molecules.39 The reaction proceeds at micelles, formed by the reagents due to their low solubility in
room temperature in MeCN to give diastereoselectively the water. The concentration of the reagent can be estimated to be
corresponding CF3-oxazinoquinolines. However, we faced a in the range of 2.5–3 M; in contrast in MeCN, the concen-
problem with the isolation of these products because using tration of the reagent is 0.16 M. Another factor accelerating the
conventional column chromatography and any solvent con- reaction is the presence of excess (50–60 equiv.) water, which
taining the traces of acids resulted in a fast epimerization to is the third component of the reaction. Additional explanation
give a mixture of diastereomers.
of such a significant acceleration of the reaction can be given
Keeping in mind a growing interest in searching for green on the basis of a careful analysis of the reaction mechanism.
alternatives in modern organic chemistry, we decided to According to the proposed mechanism, three components par-
modify the mentioned method in terms of sustainable chem- ticipate in the reaction – zwitterion A is formed as a key inter-
istry. Firstly, we focused on the solvent used in the reaction. It mediate after the addition of quinoline to trifluoroacetylacety-
was shown that the reaction proceeds in various solvents lene. Obviously, the formation of such a highly polar inter-
(DMF, DMSO, THF, 1,2-DCE, Et2O, PhMe, CH2Cl2, Et3N, and mediate is facilitated by using polar media and water is prob-
EtOAc), but MeCN was the solvent of choice due to its higher ably the best choice in this respect (Scheme 2).
yields and shorter reaction times (20 h compared to 84 h in
According to 19F NMR, the reaction proceeds very cleanly to
other mentioned ones). Although MeCN shows only modest form CF3-oxazinoquinoline as the only (3R*,4aR*)-diastereo-
toxicity, this solvent is listed as “problematic” in the overall mer. The only impurity in the crude product is CF3-ketone 2a
ranking of the CHEM21 solvent guide of “classical” solvents.40 which was used in 5% excess for the reaction. As a result, it is
Among the “recommended” solvents, water is the most attrac- not necessary to perform column chromatography to isolate
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Scheme 1 Conventional and green procedure for the synthesis of 3a.
Scheme 2 Possible mechanism of the reaction.
oxazine 3a in pure form. It is a distinct advantage of the pro- thesis in MeCN which took 144 h until completion. The reac-
posed method due to the high sensitivity of oxazines 3 towards tion of sterically hindered ketone 3i (2-chlorophenyl) with
traces of any acids, leading to isomerization and formation of quinoline proceeded more slowly (24 h) to form CF3-oxazino-
a mixture of diastereomers. First, we attempted to perform the quinoline 3i in 91% yield. It is worth noting again that in all
crystallization from EtOH–water and i-PrOH–water mixtures. the cases, reactions proceed stereoselectively to form exclusively
However, we found that epimerization took place in this case, the (3R*,4aR*)-diastereomers. As a result, this new eco-friendly
possibly due to the significant acidity of these solvents. To our procedure provided target heterocycles in more than 90%
delight, simple recrystallization of the crude residue from yield; in some cases 99% yield was reachable.
ethyl acetate–heptane mixtures is sufficient to obtain pure 3a
To demonstrate the synthetic utility of the method, we have
in high isolated yield (93%). This isolation technique produces also performed a synthesis of compound 3a on a multi-gram
a minimal amount of waste and is very simple, an undisput- scale. Thus, compound 3a was successfully prepared on a
able advantage of this particular modification. Moreover, both 1.480 g scale. The observed yield (90%) was almost the same
ethyl acetate and heptane used for purification are green envir- as the yield for 0.475 mmol reaction. The E-factor calculated
onmentally friendly solvents.
for this case (9.75) is less than 10, which is a very good value
Having such green experimental conditions in hand, we for the synthesis of fine chemicals and much better than the
performed the synthesis of several CF3-substituted oxazino- E-factor for the previously reported method (2000–3000).39
quinolines (Scheme 3). It was found that various ketones and Such a dramatic difference is explained by the much more
quinolines can be successfully involved into the reaction to give effective isolation procedure for 3a, which does not require
the corresponding CF3-oxazinoquinoline 3 in up to 99% yield. column chromatography. Moreover, water, ethyl acetate and
The reaction is general, for example, 1,8-naphtyridine was also heptane can be recycled, purified and used again for the syn-
used for the reaction with ketone 2a to form derivative 3q in thesis to reduce the E-factor even further.
94% yield. Similar to the reaction of ketone 2a and quinoline,
We also tried to reduce the amount of water used in the
all investigated reactions were accomplished in 1–2 h, i.e. by reaction to obtain a lower E-factor. Using 3 equivalents of
about 20 times faster than in MeCN. The only exception is the water, it was expected to decrease the E-factor by 1.5-fold.
less nucleophilic 3-bromoquinoline, whose transformation We also decided to scale the reaction up to 12.5 mmol. It
into CF3-oxazinoquinoline 3p required 24 h; however, this reac- was found that in this case the reaction did not proceed
tion time was still much shorter in comparison to the syn- within 2 h as in previous variation. Moreover, the reaction
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Scheme 3 The reaction of ketones 2 with quinolines 1 in water.
stopped at 95% conversion of quinoline after 1 day. As a without giving any acetal side products. Ethyl acetal 4 was pre-
result, an additional crystallization was carried out. pared by keeping 3a in absolute EtOH overnight. Interestingly,
Hence, decreasing one part of the E-factor equation unexpect- the treatment of 3a with CF3CO2H or the weaker acid AcOH in
edly increased the other part. The calculated value of the addition to the isomerization of 3a led to the formation of
E-factor was 8.36, not as low as expected. Nevertheless, the other unidentifiable products. So, only very weak acidic agents
yield of 3a was very high (90%) and 3.878 g was obtained in a are suitable for this transformation.
single run.
We attempted to prepare thioacetal by the reaction with
Next, we shifted our attention to the chemistry of CF3-oxazino- methyl 2-mercaptoacetate in MeOH. Surprisingly, after allow-
quinolines (Scheme 4). The only known fact in this field is ing the reaction mixture to stand for several days, we found a
their easy epimerization even under slightly acidic conditions 1 : 1 mixture of quinoline and vinyl thioether 5. Formation of
for example during column chromatography on silica gel39 or compound 5 was observed previously in the reaction of methyl
under crystallization from EtOH–water and i-PrOH–water mix- 2-mercaptoacetate with ketone 2.35 Taking into account the
tures (see above). In the latter case, we observed the formation presence of enamine moiety in 3a, we tried to perform reac-
of acetals of EtOH or i-PrOH, respectively. On the other hand, tions with some electrophiles. However, the reaction with
it was found that the dissolution of 3a bulky t-BuOH followed 4-fluorobenzaldehyde did take place. An attempt of trifluoro-
by the addition of water allowed the clean epimerization of 3a acylation of 3a led to the formation of a complex mixture of
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Scheme 4 Chemical properties of CF3-oxazinoquinolines.
several products. Similarly, reaction with 1 and 2 equivalents and aprotic (THF) solvents. The palladium-catalyzed hydrogen-
of bromine or with its excessive amount afforded complex mix- ation appeared to be more fruitful (Scheme 4).
tures of products.
Thus, stirring of 3a with 10 mol% of Pd/C in dry THF under
Next, we focused our attention on the CF3-semiacetal frag- H2 atmosphere (1 atm, r.t., 36 h) afforded “saturated” oxazino-
ment, which could reveal interesting transformations under quinoline 8 in 72% yield as a single diastereomer. However,
basic conditions. Thus, for example, 1,2-shift of the CF3-group under these conditions the formation of a minor admixture
was reported in similar hemiaminal formed intermediately in (about 25%) of tetrahydroquinoline 9 was observed as a result
the reaction of α-bromoenones with 1,2-diamines.41 To our of C–O bond cleavage. The shifting of the solvent to MeOH
delight, the treatment of 3a with NaOH in water at 80 °C led to allowed the suppression of such side processes. Thus, per-
a very clean formation of 2-phenylquinoline 6. Using morpho- forming the reaction in the methanolic solution led to the for-
line, which is a much weaker base, compound 3a was trans- mation of compound 11 in 84% yield as a single diastereomer.
formed into 2-phenyl-3-trifluoroacetylquinoline 7 in MeCN at Compound 11 is a methyl acetal, which is not surprising
80 °C in 6 hours. These rearrangements are under careful taking into account the formation of acetals from CF3-oxazino-
investigation, and the reaction scope as well as the possible quinoline 3a in alcohol media (Scheme 4). During monitoring
mechanism will be reported in due course.
of the reaction progress by 19F NMR, we found that the hydro-
We also investigated the reduction of CF3-oxazinoquinoline genation of the double bond in the dihydropyridine ring pro-
3a to demonstrate the access to tetrahydroquinoline deriva- ceeded much faster than the reduction of the enamine moiety.
tives.42 First, we tried to use various complex hydrides to However, we detected the formation of compound 10 in 19F
perform the reduction. However, the application of NaBH4, NMR after 14 h (overnight). Maintaining the reaction for
NaBH3CN or NaBH(OAc)3 resulted in the formation of a further 24 h led to the formation of compound 11. Enamine
complex mixture of products in both protic (MeOH and EtOH) 10 was isolated as a minor admixture (about 10%) to com-
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pound 11 during its purification, which allowed us to confirm
its structure. It should be noted that the heterocyclic motif of
Acknowledgements
2,3,4a,5-tetrahydro-1H,6H-[1,3]oxazino[3,2-a]quinoline is a very This work was supported by the Russian Science Foundation
rare type of structure and only few examples have been (grant no 18-13-00136). The authors acknowledge partial
reported quite recently.43
support in measuring of NMR from M. V. Lomonosov Moscow
In conclusion, we elaborated a green approach towards CF3- State University Program of Development. The authors
oxazinoquinolines based on the reaction of CF3-ketones with acknowledge Thermo Fisher Scientific Inc., MS Analytica
quinolines in water. It was found that the reaction proceeds up (Moscow, Russia), and personally thank Prof. A. Makarov for
to 20 times faster and permits the preparation of target hetero- providing mass spectrometry equipment for this work.
cycles in up to 99% isolated yield. Moreover, the method is
entirely diastereoselective and potentially scalable. A remark-
ably low E-factor was demonstrated. Several reactions of the
prepared CF3-oxazinoquinolines were investigated and high
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