Accessing novel fluorinated heterocycles with the hypervalent fluoroiodane reagent by solution and mechanochemical synthesis

Article abstract of DOI:10.1039/d1cc02587b

A new and efficient strategy for the rapid formation of novel fluorinated tetrahydropyridazines and dihydrooxazines has been developed by fluorocyclisation of β,γ-unsaturated hydrazones and oximes with the fluoroiodane reagent. Mechanochemical synthesis d

Full text of DOI:10.1039/d1cc02587b

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Accessing novel fluorinated heterocycles with the
hypervalent fluoroiodane reagent by solution and
mechanochemical synthesis†
Cite this: Chem. Commun., 2021,
57, 7406
Received 17th May 2021,
Accepted 14th June 2021
b
William Riley,a Andrew C. Jones,
Kuldip Singh,a Duncan L. Browne *c and
a
Alison M. Stuart
*
DOI: 10.1039/d1cc02587b
rsc.li/chemcomm
A new and efficient strategy for the rapid formation of novel with HF-pyridine.3c The synthesis of the 6-membered, fluori-
fluorinated tetrahydropyridazines and dihydrooxazines has been nated dihydrooxazines has not been reported (Scheme 1B).
developed by fluorocyclisation of b,c-unsaturated hydrazones and
Since its inception, the hypervalent iodine(III) reagent, fluoro-
oximes with the fluoroiodane reagent. Mechanochemical synthesis iodane 1 (Scheme 1C), has emerged as an excellent fluorinating
delivered fluorinated tetrahydropyridazines in similar excellent reagent with a wide range of applications.4,5 In many cases,
yields to conventional solution synthesis, whereas fluorinated dihy- fluoroiodane 1 exhibits differing reactivity to that observed with
drooxazines were prepared in much better yields by ball-milling.
fluoraza reagents such as Selectfluor. We recently employed
fluoroiodane 1 in the synthesis of fluorinated lactones using
Over 85% of small molecule pharmaceuticals approved by the either AgBF46a or hexafluoroisopropanol (HFIP)6b to activate the
FDA in 2019 contained a nitrogen-based heterocycle and over a fluoroiodane reagent. Looking to further explore the utility of
quarter of all FDA approved drug molecules on the market this reagent in fluorocyclisations, we investigated the synthesis
contain at least one fluorine atom.1a The prominence of of fluorinated tetrahydropyridazines and dihydrooxazines.
heterocycles comes from their activity in vivo, where, specifi- We also applied ball-milling to the fluorocyclisations since
cally their structure provides rigidity to molecular shape and
enables effective binding. The pharmaceutical industry is par-
ticularly interested in heterocycles with a high sp3 content1b
and the C–F bond has a great influence on the pharmacokinetic
properties of biologically active molecules.1c
Fluorinated N-heterocycles can be accessed in a single step
by intramolecular fluorocyclisations of unsaturated substrates
containing an internal nucleophile. The fluorocyclisations
of b,g-unsaturated hydrazones with Selectfluor produced the
5-membered, fluorinated dihydropyrazoles (Scheme 1A).2 In
one report, fluorinated tetrahydropyridazines were formed
along with the dihydropyrazoles when R was an aryl group.2
Similarly, the fluorocyclisations of b,g-unsaturated oximes
formed the 5-membered, fluorinated dihydroisoxazoles using
either Selectfluor,3a,b or hypervalent iodine reagent, PhI(OPiv)2,
a School of Chemistry, University of Leicester, Leicester, LE1 7RH, UK.
E-mail: Alison.Stuart@le.ac.uk
b Cardiff Catalysis Institute, School of Chemistry,
Cardiff University, Cardiff, CF10 3AT, UK
c School of Pharmacy, UCL, London, WC1N 1AX, UK.
E-mail: Duncan.Browne@ucl.ac.uk
Scheme 1 (A) Synthesis of fluorinated dihydropyrazoles. (B) Synthesis of
fluorinated dihydroisoxazoles. (C) Synthesis of fluorinated tetrahydropyr-
idazines and dihydrooxazines.
† Electronic supplementary information (ESI) available: Experimental procedures
and NMR spectra. CCDC 2083051–2083056. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/d1cc02587b
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Table 1 Optimisation of b,g-unsaturated hydrazone fluorocyclisationa
organocatalysis.10b Herein, we report the regioselective synth-
esis of novel fluorinated 6-membered heterocycles, tetrahydro-
pyridazines and dihydrooxazines, alongside the use of
mechanochemistry to minimise halogenated solvents and to
improve the yields in the preparation of fluorinated
dihydrooxazines.
We began our studies by investigating the fluorocyclisation
of hydrazone 2a. To our delight, 2a was fluorocyclised at room
temperature in 4 hours using fluoroiodane 1 (1.5 equiv.) with
AgBF4 (1 equiv.) in CH2Cl2 to produce the desired fluorinated
tetrahydropyridazine 3a in 91% yield (Table 1, entry 1). The
reaction time could be reduced to just 15 minutes with minimal
decrease in yield (entry 3). Alternatively, the amount of AgBF4
could be decreased to 0.2 equivalents in a 1 hour reaction to
form the product in 86% yield (entry 4). On further investiga-
tion of solvent and temperature (entries 5–10), a set of metal-
free conditions were identified using HFIP as the solvent and
activator of fluoroiodane 1 giving 3a in 93% yield after only
15 minutes (entry 10). Notably, whilst use of acetonitrile as
solvent did furnish the desired fluorinated product 3a, Ritter
product 4 was also formed in 23% yield suggesting that a
tertiary carbocation is a key intermediate in the fluorocyclisa-
tion. In entries 7 and 8 where product yield was lower at 40 1C,
mechanochemical synthesis can minimise solvent requirement elimination byproduct 5 was also observed in 10–15% yield.
and in many cases, can provide enhanced and altered
Using mechanochemistry the unsaturated hydrazones could
reactivity.7 Ball-milling has shown promise in bromocyclisa- efficiently undergo fluorocyclisations with fluoroiodane 1
tions8 and in fluorination reactions, where Selectfluor can (1.5 equiv.) and just 2 equivalents of HFIP (an 8 fold reduction
selectively mono- or di-fluorinate 1,3-dicarbonyl compounds,9 in the amount of HFIP required, ESI,† Table S3) to provide
fluorinate pyrazolone rings,10a and be used in asymmetric an alternative, solvent minimised method. For this protocol,
Scheme 2 Scope of 5-fluorinated tetrahydropyridazine synthesis by solution and mechanochemical synthesis.
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Table
fluorocyclisation
2
Mechanochemical optimisation of b,g-unsaturated oxime
a 10 mL stainless steel milling jar was used with a 2.5 g
stainless steel milling ball, and the reaction mixture was milled
at 30 Hz for 15 minutes.
With optimal conditions for both a solution and ball-milling
method in hand, application to a range of unsaturated hydra-
zones was explored (Scheme 2). The reaction was tolerant for a
series of aryl substituted hydrazones (Scheme 2, 3a–h) with
examples of both electron-donating (3e) and electron-with-
drawing aryl groups (3b). Although synthesis of the thiophene
substituted hydrazone proceeded efficiently (3h), the aromatic
byproduct, 5-methyl-3-thiophen-2-yl pyridazine, was also formed
in 16% yield. The fluorocyclisation proved successful on alkyl
substituted hydrazones (3i–k) including benzyl and the more
hindered isopropyl hydrazones. Bis-tetrahydropyridazine (3l)
was prepared by a double fluorocyclisation. In all cases,
metal-free protocols could be employed and delivered similar
yields in comparison to reactions containing AgBF4. The
mechanochemical approach was applied to a small range of
substrates (3b–e, 3k and 3l) and provided comparable excellent
yields to those observed in solution demonstrating an efficient,
solvent minimised method. Further studies revealed that
catalytic amounts of HFIP (0.1 equiv.) activated fluoroiodane
1 in CH2Cl2 and delivered fluorinated tetrahydropyridazine 3a
in 90% yield (Scheme S1, ESI†).
Initial results with b,g-unsaturated oximes demonstrated
that they could undergo fluorocyclisation to form dihydro-
oxazines. This class of fluorinated heterocycle has not been
reported previously. After optimisation for traditional solution
conditions (ESI,† Table S4), dihydrooxazine 7a could be formed
in 46% yield after 15 minutes with 1 equivalent of AgBF4
(Table 2A). Notably, dihydroisoxazole 8, intercepted by the
benzyl-alcohol backbone of the fluoroiodane reagent, was also
isolated as a side product in 15% yield. In an attempt to
improve yield and selectivity towards the desired product,
attention was turned to mechanochemical techniques com-
mencing with the conditions used for hydrazone fluorocyclisa-
tions (Scheme 2). Fluorocyclisation of unsaturated oxime 6b
using fluoroiodane 1 proceeded to give 36% of the desired
product with 2 equivalents of HFIP (Table 2, entry 1). Increased
loading of HFIP improved the yield of dihydrooxazine 7b, but
also increased the amount of unwanted dihydroisoxazole 9
(entry 2). A small amount of oxazine 10, resulting from elimi-
nation, was also observed. Switching to AgBF4 showed
decreased activity initially (entry 3). However, using AgBF4 with
5 equivalents of CH2Cl2 provided a dramatic improvement in
the yield of dihydrooxazine 7b (80% isolated yield), and
reduced the formation of side products 9 and 10 to 1% (entry 5).
Further studies on the two additives and reaction time revealed
that 2 equivalents of AgBF4 and 5 equivalents of CH2Cl2 in a
1 hour reaction was optimal (entries 6–10). In the absence of
HFIP or AgBF4, the reaction showed no activity and returned
quantitative amounts of oxime 6b (entry 11).
Scheme 3 (A) Scope of 5-fluorodihydrooxazine synthesis. (B) Proposed
mechanism.
A range of b,g-unsaturated oximes was examined and under
traditional solution conditions, aryl unsaturated oximes could
undergo fluorocyclisations in moderate yield (Scheme 3A, 7a–7d,
42–53%). However, applying mechanochemical conditions to
these substrates greatly improved the yields delivering products
7a–7d in 71–80% yield. Alkyl oximes could also be tolerated
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is a complementary reagent for diversifying fluorination
methodology. Mechanochemistry has provided a dramatic
improvement in the yield and selectivity to fluorinated
dihydrooxazines, and in so doing has highlighted that mechan-
istically complex reactions can be readily achieved in a ball-mill.
Conflicts of interest
There are no conflicts to declare.
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Chem. Commun., 2021, 57, 7406–7409 | 7409