Synthesis of 5-(Fluoroalkyl)isoxazole Building Blocks by Regioselective Reactions of Functionalized Halogenoximes

Article abstract of DOI:10.1021/acs.joc.9b02264

A comprehensive study on the synthesis of 5-fluoroalkyl-substituted isoxazoles starting from functionalized halogenoximes is reported. One-pot metal-free [3 + 2] cycloaddition of CF₃-substituted alkenes and halogenoximes bearing ester, bromo, c

Full text of DOI:10.1021/acs.joc.9b02264

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Article
Synthesis of 5-(Fluoroalkyl)isoxazole Building Blocks by
Regioselective Reactions of Functionalized Halogenoximes
Bohdan A. Chalyk, Kateryna V. Hrebeniuk, Yulia V. Fil, Konstantin S. Gavrilenko,
Alexander B. Rozhenko, Bohdan V. Vashchenko, Oleksandr V. Borysov, Angelina V.
Biitseva, Pavlo S. Lebed, Iulia Bakanovych, Yurii S. Moroz, and Oleksandr O. Grygorenko
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02264 • Publication Date (Web): 18 Oct 2019
Downloaded from pubs.acs.org on October 19, 2019
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The Journal of Organic Chemistry
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Synthesis of 5-(Fluoroalkyl)isoxazole Building Blocks
by Regioselective Reactions of Functionalized
Halogenoximes
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†
,‡
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†
†,§
Bohdan A. Chalyk, Kateryna V. Hrebeniuk, Yulia V. Fil, Dr. Konstantin S. Gavrilenko,
Dr. Alexander B. Rozhenko, Bohdan V. Vashchenko Dr. Oleksandr V. Borysov,†,‡
‡
†,§
†
,§
†,§
†,§
†,#
Dr. Angelina V. Biitseva, Dr. Pavlo S. Lebed, Iulia Bakanovych, Dr. Yurii S. Moroz,
Dr. Oleksandr O. Grygorenko†,§,*
†
Enamine Ltd. (www.enamine.net), Chervonotkatska Street 78, Kyiv 02094, Ukraine
‡
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv
2660, Ukraine
0
§
Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine
#
Chemspace, Ilukstes iela 38-5, Riga, LV-1082, Latvia
gregor@univ.kiev.ua
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
Abstract. A comprehensive study on the synthesis of 5-fluoroalkyl-substituted isoxazoles starting from
functionalized halogenoximes is reported. One-pot metal-free [3+2] cycloaddition of CF -substituted
3
alkenes and halogenoximes bearing ester, bromo, chloromethyl, and protected amino groups was
developed for the preparation of 5-trifluoromethylisoxazoles. The target 3,5-disubstituted derivatives
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were obtained in regioselective manner in good to excellent yield on up to 130 g scale. 5-Fluoromethyl-
and 5-difluoromethylisoxazoles were synthesized by late-stage deoxofluorination of the corresponding
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-hydroxymethyl or 5-formyl derivatives, respectively, in turn prepared via metal-free cycloaddition of
halogenoximes and propargylic alcohol. An alternative approach based on nucleophilic substitution in
-bromomethyl derivatives was found to be more convenient for the preparation of 5-
5
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fluoromethylisoxazoles. Reaction of isoxazole-5-carbaldehydes with the Ruppert – Prakash reagent was
used for the preparation of (,,-trifluoro--hydroxyethyl)isoxazoles. Utility of described approaches
was shown by multigram preparation of side-chain functionalized mono-, di- and trifluoro-
methylisoxazoles, e.g. fluorinated analogues of ABT-418 and ЕSI-09.
regioselective
3+2] cyclizations
R
R
R
F
F
[
F
F
N
F
N
F
N
X
O
O
R
up to 150 g scale
10 examples
X = OH, Br
O
Ri
O(H)
1
24 steps
O
R
R
EWG
R
Hal
OH
EWG
Br
CF3
Rf
EWG
O
F
or
N
f
N
R = CF3, CHF2
N
N
Rf
O
F
O
Rf
O
F
R = N-Boc-amino acid-derived moiety, CO2Et, CH2Cl, CH2OH, Br, Ar
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The Journal of Organic Chemistry
Introduction
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Isoxazole ring has been recognized as an essential heterocyclic scaffold for organic synthesis and
medicinal chemistry.1–3 In particular, nearly two dozens of pharmaceuticals containing 3- or 5-
methylisoxazole motif were approved by FDA to date, and many more have reached various phases of
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clinical studies (e.g. β-lactam antibiotics,4,5 sulfonamide antibacterials, antidepressants, antirheumatic
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drugs, , anti-inflammatory, antiviral, or hypoglycemic11 agents, fungicides12 and other classes)13,14
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(Figure 1). Introducing fluorine atoms into alkyl substituents is one of the most powerful design tools in
drug discovery. Such modification often improves physicochemical characteristics and pharmacokinetic
properties of the compounds.15,16
O
N
SO NHR
2
H
N
H
R2
S
O
R1
Ph
N
O
HO
N
O
O
1
2
Valdecoxib
, R = H
Oxacillin, R = R = H;
1
2
(anti-inflammatory drug);
Parecoxib, R = C(O)Et
(its prodrug)
Cloxacillin, R = H, R = Cl;
1
2
Dicloxacillin, R = R = Cl;
1
2
Flucloxacillin, R = Cl, R = F
O
N
O
O
HN
CF3
N
S
O
N
H O
Leflunomide
antirheumatic drug)
NH2
(
Sulfafurazole
(antibacterial agent)
O
N
N
NH
NHBn
H
O
N
N
O
N
ABT-418
drug candidate
O
(
Isocarboxazid
antidepressant)
Epiboxidine
(studied as
analgetic)
with nootropic,
neuroprotective and
anxiolytic effects)
(
Figure 1. Some biologically active compounds bearing a 3- or 5-methylisoxazole moiety.
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It is not surprising therefore that synthesis of fluoroalkyl-substituted isoxazoles have attracted
significant interest. A classical approach to the synthesis of these compounds relies on the
heterocyclization reaction of fluorinated 1,3-bis-electrophiles and hydroxylamine (Scheme 1, A).17–23
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Similar method involves condensation of enolizable oximes with trifluoroacetates (Scheme 1, B). In
addition to that, deoxofluorination of the oxygen-containing isoxazoles, e.g. alcohols or aldehydes, was
described (Scheme 1, C).25,26 An alternative approach includes [3+2] cycloaddition27–32 of fluoroalkyl-
substituted alkenes,33–35 alkynes35–37 or enolizable ketones38–40 and generated in situ nitrile oxides
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(Scheme 1, D). To the best of our knowledge, many examples of aforementioned [3+2] cycloadditions
were not regioselective under reported conditions.41–45 In other cases, when 5-(fluoroalkyl)isoxazoles
were the desired product, the observed regioselectivity led to target compounds only as minor
product.35,37,46 Moreover, limited substrate scope was typically demonstrated, often including only aryl-
substituted nitrile oxides.
HO NH2
+
OH
N
f
3
+ R CO R
O
O
2
R1
A
C
B
D
Rf
R1
Ri
O
f
R : fluoroalkyl group
and their synthetic
equivalents
Rf
i
R : any other groups
N
(i = 1, 2); alkyl (i = 3)
Ri
N
Rf
Rf
R1
(
H)O
O
R2
(LG)
Rf
R1
N O
+
or
O
EWG
Scheme 1. Known approaches to fluoroalkyl-substituted isoxazoles
In line with our continuous efforts to synthesize fluorinated oxazoles,47–50 in this work we report a
comprehensive study on the regioselective synthesis of various 5-(fluoroalkyl)isoxazoles via the [3+2]
cycloaddition approach involving halogenoximes as the nitrile oxide source, focusing mainly on the
preparation of functionalized substrates (e.g. bearing a protected amino group). In addition to that, we
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have aimed at expanding of chemical space covered by fluorinated isoxazoles with a series of small-
molecule building blocks accessible on multigram scale.
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Our previous experience with [3+2] cycloadditions showed that regioselectivity of the reaction can be
controlled by using alkenes bearing a leaving group (e.g. bromo or dialkylamino substituents) as the
51
starting materials. To date, only a few examples of similar reactions with trifluoromethyl-substituted
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substrates were described in the literature, being limited to simple alkyl- or benzonitrile oxides and ,-
unsaturated esters (Scheme 2).33,34,52
EtO C
LG
LG = Br, OEt, OAc,
OBz, OTs, NHCbz
2
Ph
Cl
CF3
N
N
Et N, 379%
3
OH
R
CO Et
2
R1
N O
EtO C
N
2
N
Rf
O
R
O
Rf
3
Et N, POCl3
R = Me, Et, Ph
Rf = CF , CF Br,
O
6
192%
3
2
(
CF ) Cl
2 3
Scheme 2. Known syntheses of 5-(fluoroalkyl)isoxazoles by [3+2] cycloaddition of nitrile oxides and
,-unsaturated esters

Results and discussion
Synthesis of 5-(trifluoromethyl)isoxazoles. In addition to that, reaction of chloroxime 1a and 2-
53
bromo-3,3,3-trifluoroprop-1-ene (2) in the presence of Et N in Et O was disclosed in a patent. In our
3
2
hands, the latter transformation was not successful under the conditions reported (the corresponding
furoxan was obtained as the major product); nevertheless, reaction of 1a and 2 occurred in the presence
of NaHCO in EtOAc as the solvent (Table 1, Entry 1). Using three-fold excess of 2 was necessary to
3
achieve the complete conversion; with smaller amounts of 2, significant nitrile oxide dimerization was
Table 1. Synthesis of 5-(trifluoromethyl)isoxazoles 3a–o
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R
R
Cl
NaHCO , EtOAc
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9
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5
5
5
5
5
5
5
6
3
+
N
F3C
Br
rt, overnight
095%
N
OH
CF3
O
3ao
4
1ao
2 (3 eq)
Yield, %a
Entry Chloroxime
R
Product
3a
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
CO Et
69
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Ph
3b
44
4-MeOC H
3c
74
6
4
4-FC H
3d
73
6
4
2-thienyl
3e
40
3f
89 (73b)
BocHN
7
8
9
1g
1h
1i
3g
3h
3i
72
76
85
BocHN
BocHN
BocHN
10
11
1j
3j
42 (81c)
94
BocN
1k
3k
N
Boc
1
1
2
3
1l
3l
95
N
Boc
1m
1n
3m
3n
57
40
BocN
O
14
N
Boc
1
5
1o
O
3o
42
N
Boc
a
Yields of isolated products b At 160-g scale of 1f, 2.5-fold excess of 2 was used, which resulted in slightly diminished
c
yield of the product The reaction was performed in EtOAc – THF (1:1, v/v) due to limited solubility of 1j in EtOAc
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observed. On the contrary, using higher excess of 2 did not improve the yield of the product. The target
compound 3a was isolated in 69% yield on up to 100 g scale after distillation in vacuo.
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It should be noted that alkene 2 can be considered as the synthetic equivalent of 3,3,3-trifluoroprop-1-
yne, which is hardly accesssible and inconvenient to handle due to its low boiling point (–48…–47 °C).
Taking into account the literature examples of [3+2] cycloadditions of benzonitrile oxide shown in
Scheme 2,33,34,52 we have checked the developed procedure with aryl chloroximes 1b–e (Table 1, Entries
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2
–5). The title products 3b–e were obtained as single regioisomers in 40–74% yield after distillation in
vacuo (3b) or chromatographic purification (3c–e). The method was also extended to amino acid-
5
4
derived chloroximes 1f–o, prepared using a protocol reported by our group previously. Reaction of 1f–
o and 2 under the conditions described above led to the formation of 5-(trifluoromethyl)isoxazoles 3f–o
bearing a protected amino function in 40–95% yield (Table 1, Entries 6–15). It is important to outline
that the target products 3 could be obtained on up to 150 g scale (checked for 3f, 73% yield).
Interestingly, reaction of alkene 2 with dibromo derivative 4 in the presence of NaHCO in less polar
3
CH Cl resulted in the formation of isoxazoline 5 (63% yield) (Scheme 3). Transformation of 5 into the
2
2
product 6 required using NaHCO in EtOAc (or K CO , CH Cl , rt, 1 week, 50% yield). Although
3
2
3
2
2
formation of the intermediates of the type 5 bearing cyclic substituents or ester moiety was postulated
for the [3+2] cycloadditions with nitrile oxides previously, but only a few examples of their isolation
were reported to date.55,56 Also, this transformation could be performed one-pot using 3-fold excess of
NaHCO in EtOAc (61% yield).
3
NaHCO , EtOAc, rt, overnight, 61%
3
2
Br
NaHCO3
EtOAc, rt
Br
Br
Br
F3C
Br
NaHCO , CH Cl
2
Br
N
N
overnight
57%
N
3
2
CF3
OH
O
CF3
O
rt, overnight
63%
4
5
6
Scheme 3. Synthesis of 3-bromo-5-(trifluoromethyl)isoxazole (6)
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It is important to outline that in all cases studied, only 3,5-disubstituted isomers 3a–o and 6 were
obtained. The structure of the products was confirmed proven by single crystal X-ray diffraction
analysis of the compound 3h (Figure 2).
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2
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9
1
1
1
1
1
1
1
1
1
1
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9
0
1
2
3
4
5
6
7
8
9
0
BocHN
CF3
N
O
Figure 2. Molecular structure of 3h (thermal ellipsoids are shown at 50% probability level)
The regioselectivity of the process might be governed by steric and/or electronic factors. In particular,
the transition state TS1 leading to the formation of 3,4-disubstituted isoxazolines 7 and corresponding
isoxazoles 8 is unfavorable as compared to TS2 (leading to 3 via isoxazolines 9) due to steric repulsion
between the R substituent, the trifluoromethyl group and the bromine atom (Scheme 4).
N
R
N O
R
N
R
O
O
F3C
Br
F3C
H
Br
H
F3C
TS1
unfavorable
7
8, not observed
R
N O
INT
OH
N
+
F3C
Br
generated
in situ
R
Cl
2
1
N
N
R
N O
R
R
O
O
CF3
H
Br
CF3
H
CF3
Br
TS2
9
3
Scheme 4. A plausible mechanism of the reaction between 1 and 2
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In order to elucidate the observed regioselectivity, the reaction was studied using quantum chemical
1
2
calculations (RI-BP86), modeling the preferable formation of derivatives 9b and 9f compared to the
isomeric 7b and 7f. Since these structures contain sterically crowded t-Bu group (9f) or aromatic moiety
(9b) disposed to interactions with large contributions of electron dispersion effects. This can
significantly influence the E and G values computed using conventional DFT methods. Taking this
fact into account, the structures corresponding to local minima were additionally optimized using
Grimme’s RI-B97-D approximation having a dispersion correction. The calculations predicted negative
energies of formation (either E or G) for cyclic products of the both types. Nevertheless, formation
3
4
5
6
7
8
9
1
1
1
1
1
1
1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
9
b and 9f appeared to be more favorable as compared to isomeric 7b and 7f (see Supporting
information, Tables S1, S2 for more details). Therefore, the calculations confirmed formation of the
products of type 9b and 9f in the thermodynamically controlled cyclization reaction. Considering
dispersion interactions using the RI-B97-D functional slightly reduces the E and G negative values
(Tables 2 and S3).
Geometries of the transition states TS2-b and TS2-f are shown in Table 2. The corresponding
activation energy values are by 3.9–4.3 kcal/mol lower than for the isomeric TS1-b and TS1-f. Hence
almost exclusive formation of the cyclization products 9b and 9f is favorable, which is observed in the
experiments. Moderate activation energy magnitudes estimated at the DFT level of approximation
(G = 25.6 and 23.0 kcal/mol for 9b and 9f, respectively) agree well with rather soft reaction conditions
used. Thus, for the given set of the substituents, both thermodynamic and kinetic factors direct the
process towards the same type of products in the studied reactions.
Relative stability of the products is driven by similar electronic and steric factors determining higher
stability for 9b and 9f relative to their regioisomers 7b and 7f. The steric factor in the transition states is
probably of high importance. This is best seen by comparing the conformations of TS1-b and TS2-b
(Table 2).
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Table 2. Optimized (RI-BP86) structures of TS1-b, TS2-b, TS1-f, and TS2-f. The G values are
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
given in kcal/mol relative to the starting reactants.
‡
Transition state
RI-B97-D optimized structure
G (kcal/mol)
TS1-b
29.5
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
TS2-b
TS1-f
25.6
26.7
TS2-f
23.0
In TS2-b, the phenyl moiety is efficiently conjugated with the C–N–O fragment, whereas in TS1-b,
the aromatic ring is orthogonal to it. Noteworthy, the located TS2 structures evidence rather
synchronous [3+2] cycloaddition: the C–C and C–O distances corresponding to the newly formed bonds
are comparable (2.196 and 2.489 Å for TS2-b, and 2.176 and 2.525 Å for TS2-f).
Frontier molecular orbitals (FMO), i.e. the highest occupied molecular orbital (HOMO) and the
lowest unoccupied molecular orbital (LUMO) for the starting material 2 and corresponding
intermediates INT with corresponding orbital energies are shown in Figure 3. Two types of [3+2]
HOMO – LUMO interactions are possible: HOMO(INT) – LUMO(2) vs HOMO(2) – LUMO(INT).
The smaller E values were found for the combinations of molecular orbitals HOMO(INT-b)–
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LUMO(2) and HOMO(INT-f)–LUMO(2) (13.53 and 12.10 eV, respectively), which corresponds to the
FMO interaction between the highest occupied molecular orbital of the 1,3-dipole and the lowest
unoccupied molecular orbital of the dipolarophile (the normal-electron demand). An alternative
possibility for the 1,3-dipolar cycloaddition reactions, the interaction between the LUMO of the 1,3-
dipole and the HOMO of the dipolarophile (the inverse-electron demand), is characterized here by
higher E values: 14.71 and 12.62 eV, respectively. Thus, the first type of interaction is expected in the
considered cases.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
LUMO(INT-b), E = 4.166 eV
LUMO(2), E = 3.140 eV
LUMO(INT-f), E = 2.084 eV
HOMO(INT-b), E = –10.39 eV
HOMO(2), E = –10.545 eV
HOMO(INT-f), E = –8.964 eV
57
Figure 3. Chemissian plots of FMOs for the 1,3-dipole molecules (INT-b and INT-f) and for the
dipolarophile 2 calculated at the RHF/6-31G*//RI-B97-D/TZVP level of theory.
As can be seen from the FMO graphical representation, contributions from the corresponding atoms
into HOMO(INT-b,f) and LUMO(2) participating in the reaction are very similar and hence, the orbital
overlapping extent cannot explain the observed regioselectivity of the process. Additional information
can be derived analyzing the natural bond orbital (NBO) atomic charges58,59 in the reacting species
(Figure 4). The shown transition states demonstrate favored C–C interaction (attraction of positive and
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negative charges) and less pronounced C–O repulsion than in the alternative structures. Thus, the charge
distribution favors the product structures identical to those found experimentally.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0.123
Ph
0.168
BocHN
0.161
0
.156
N
N
O 0.327
O 0.328
CF3
0.186
CF3
0.186

0.365
0.365
Br
INT-f + 2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Br
INT-b + 2
Figure 4. NBO atomic charges in the reagents (BP86/TZVP//RI-B97-D/TZVP level of theory).
Further studies of 5-trifluoromethyl derivatives obtained above included preparation of bulding blocks
relevant to drug discovery, i.e. carboxylic acid 10, alcohol 11, chloride 12, and amines 13. Synthesis of
the corresponding carboxylic acid 10 from ester 3a was found to be challenging (Scheme 5). Reactions
of 3a with TMSBr or TMSI in HOAc, as well as KHMDS or TMSOK were unfruitful due to low yields
of 10 and/or long reaction times (up to 72 h).
DIBAL,
CH2Cl2
5 to 0 °C
OH
N
NaOH,
MeOH, EtO C
0 °C, 1 h
HO C
2
2
N
then HCl
8%
N
1 h
81%
CF3
CF3
CF3
O
10
O
3a
O
6
11
SOCl , DMF
2
Cl
N
2
CH Cl
2
2
Cl
64%
Br
CF3
Cl
N
NaHCO , EtOAc
rt, overnight, 46%
3
CF3
OH
O
1p
12
Scheme 5. Synthesis of building blocks 10–12
Thus, compound 10 was obtained in 68% yield via slow dropwise addition of 3a solution in MeOH to
the homogenous solution of NaOH in MeOH at 0 °C. It should be noted that the aforementioned
reaction was highly exothermic.
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Reduction of 3a with LiAlH was unfruitful in all attempts; thus, the corresponding alcohol 11 was
4
1
2
smoothly synthesized from 3a in 81% yield via reaction with DIBAL in CH Cl at –5 to 0 °C for 1 h,
2
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
followed by aq HCl work-up.
In turn, preparation of alkylating agent 12 relied on the reaction of hydroxymethyl derivative 11 with
SOCl . The yield of the product 12 was moderate (64%; 30% overall yield from 1a); the use of other
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
reagents such as (COCl) or NCS – PPh did not improve the reaction outcome. More efficient approach
2
3
to 12 relied on direct [3+2] cycloaddition reaction of chloroxime 1p and 3-fold excess of 2 (600 g),
which led to the target derivative 12 in 46% yield on 100 g scale.
In turn, deprotection of the Boc derivatives 3f–m upon action of generated in situ methanolic HCl led
to aliphatic amines 13f–m (92–98% yield, isolated as hydrochlorides except 13i, which was obtained
and purified as a free base in 51% yield) (Table 3). It is important to stress out that the building blocks
1
3fHCl, 13i, 13k–lHCl could be obtained at multigram scale (up to 30 g).
Table 3. Synthesis of amines 13f–m
HCl
generated
from AcCl)
= R
(
N
Boc
H N
2
MeOH
9298%
Cl
N
N
CF3
CF3
O
O
.
3fm
1
3fm HCl
3i (base, 51% yield)
1
Entry
1
Boc derivative
R
Product
Yield, %a
3f
13fHCl
95
93
BocHN
2
3
4
5
3g
3h
3i
13gHCl
13hHCl
13i
BocHN
92
BocHN
BocHN
51b
95
3j
13jHCl
BocN
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6
7
8
3k
3l
13kHCl
97
98
92
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
N
Boc
13lHCl
N
Boc
3m
13mHCl
BocN
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
b
Yields of isolated products Purified and isolated as a free base
Synthesis of other 5-(fluoroalkyl)isoxazoles. Since unlike 2-bromo-3,3,3-trifluoroprop-1-ene (2), the
corresponding mono- and difluorinated alkenes are not readily available, we have switched to the
deoxofluorination strategy for the preparation of the 5-(fluoromethyl)- and 5-
(
difluoromethyl)isoxazoles. Only a few examples of similar transformations were reported in the
literature, including synthesis of the compounds 14 and 15 (Scheme 6).25,26
We anticipated that alcohols 16 and the corresponding aldehydes 17 (obtained by oxidation of 16)
might be proper key intermediates for the preparation of the target products 18 and 19, respectively. In
turn, synthesis of hydroxymethyl derivatives 16 might rely on [3+2] cycloaddition of functionalized
halogenoximes 1 and propargylic alcohol. To the best of our knowledge, only a single example of
analogous transformation which involved metal catalysis was mentioned in the literature to date.60
In this work, a transition metal-free version of this reaction was used. In particular, it was found that
chloroximes 1f–m smoothly reacted with propargyl alcohol under the standard conditions (NaHCO3,
EtOAc, rt) to give the target products 16f–m in 84–96% yield (Table 4). Deoxofluorination of 16f–l
with morph-DAST in CH Cl at –10 °C gave the title isoxazoles 18f–l in low to moderate yields (6–
2
2
3
1% after chromatographic purification).
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The Journal of Organic Chemistry
O
N
O
Known
examples
1
2
3
4
5
6
7
8
9
DAST
CH Cl2
X
X
OH
2
F
N
4
055%
O
O
X = OEt, NHAr
14
BocN
BocN
DAST
N
N
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CH Cl2
2
F
F
N
O
73%
N
O
O
15
R : amino acid-derived substituent
This work
R
R
R
F
F
O(H)
16 or 17
N
N
N
O
F
19
O
O
1
8
Scheme 6. Synthesis of 5-((di)fluoromethyl)isoxazoles 18 and 19 via deoxofluorination
To obtain the difluoromethyl-substituted products 19, alcohols 16f–m were first oxidized the
corresponding aldehydes 17g–m with PCC (43–80% yield). Oxidation with the Parikh – Doering
reagent gave better reaction outcome (69–83% yield, except 17j obtained in 14% yield); meanwhile,
using the Dess – Martin reagent was unfruitful due to low yields of the products. Aldehyde 17f appeared
Table 4. Synthesis of 5-((di)fluoromethyl)isoxazoles 18–21
=
R
O
N SF3
OH
HCl
+
N
N
N
Boc
H N
2
Boc
Cl NaHCO3
EtOAc, rt
OH
Boc
CH Cl
MeOH
9295%
Cl-
2
2
OH
F
F
N
N
631%
N
N
O
O
O
.
8496%
1fm
16fm
18fl
20il HCl
PCC, SiO , CH Cl or
2
.
2
2
DMSO, Py SO , Et N, CH Cl
3
3
2
2
O
N SF3
+
N
Boc
HCl
H N
2
N
Cl-
Boc
CH Cl
F
MeOH
F
2
2
O
N
O
N
O
N
2361%
9198%
O
F
F
21g l.
HCl
1
7gm
19gl

R
Alcohol
Product
16 (yield, (yield, %)
18 Product
20HCl
Aldehyde 17 Product
(yield, %) 19 (yield, 21HCl
Product
a
a
a
a
%
)
(yield, % )
% )
(yield, % )
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b
c
N/Ad
N/Ad
17g (66 , 78 )
N/Ad
N/Ad
1
2
16f (94)
16g (96)
18f (6 , 93 )
BocHN
BocHN
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
18g (10 , 97 ) N/Ad
b
c
e
f
19g (23)
21gHCl
(96)
b
c
e
f
3
4
5
6
16h (95)
16i (91)
16j (84)
16k (90)
18h (12 , 98 ) N/Ad
17h (67 , 76 )
19h (25)
19i (28)
19j (35)
19k (53)
21hHCl
BocHN
BocHN
(95)
b
c
e
f
18i (30 , 93 ) 20iHCl (92) 17i (80 , 83 )
21iHCl
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(93)
18j (16 , 96 ) N/Ad
b
c
17j (43 , 14 )
e
f
21jHCl
91)
BocN
(
18k (31b)
18l (25b)
17k (78 , 81 )
e
f
20kHCl
94)
21kHCl
(96)
(
N
Boc
e
f
7
8
16l (92)
20lHCl (95) 17l (75 , 80 )
19l (61)
21lHCl
(98)
N
Boc
16m (85) 18m (N/Ad)
N/Ad
17m (55 , 69 ) N/Ad
e
f
N/Ad
BocN
a
b
Yield of isolated products Yield of isolated products given for the deoxofluorination reaction (Morph-DAST, CH
2
Cl
2
, –
3
5 °C to –10 °C, 1.5 h) c Yield of isolated products given for the Finkelstein reaction (KHF
, MeCN, 18-crown-6, reflux,
2
d
overnight) The compound was not prepared due to the low yield of the starting material on the previous step of the reaction
sequence e Yield of isolated products of oxidation performed with PCC, SiO
oxidation via using of DMSO, PySO , Et N.
, CH
Cl
f
Yield of isolated products of
2
2
2
3
3
to be too unstable to be isolated, whereas other compounds of this series could be isolated and stored at
4 °C. Deoxofluorination of 17g–l under the aforementioned conditions led to the formation of 19g–l in
+
moderate yields (23–61%). Deprotection of 18 and 19 with methanolic HCl proceeded smoothly and
gave building blocks 20 and 21, respectively, in 91–98% yield.
Due to the low yields of the deoxofluorination of alcohols 16f–h, 16j and 16m, the Finkelstein
reaction was successfully applied for preparation of CH F-derivatives 18 (Scheme 7). The bromide
2
substitution of 22f–h, 22j and 22m proceeded in 93–98% yield by refluxing of the substrate, KHF and
2
1
8-crown-6 as catalyst in MeCN. Applying dibenzo-18-crown-6 as a phase-transfer catalyst did not
improve the yields of 18.
In turn, bromides 22 were obtained in 61–72% yield by cycloaddition reaction of chloroxime 1f–h, 1j
and 1m and freshly distilled propargyl bromide in the presence of 1.1-fold excess of NaHCO in EtOAc.
3
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This approach was also extended to chloroxime 1a to obtain isoxazole 22a (68% yield), which was used
for the preparation of fluoromethyl derivative 18a bearing an ester moiety (65% yield).
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
R
KHF , MeCN
R
R
Cl
2
Br
18-crown-6
Br
F
N
N
N
NaHCO3
EtOAc, rt
172%
reflux
6598%
OH
O
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1a, 1fh,
j or 1m
22a, 22fh,
22j or 22m
18a, 18fh,
18j or 18m
(Table 4)
6
1
EtO C
2
2a, 68%, R =
2
22f, 61%, R =
22h, 72%, R =
BocHN
22g, 71%, R =
BocHN
BocHN
22j, 70%, R = BocN
22m, 71%, R = BocN
Scheme 7. Synthesis of 18 via the Finkelstein reaction of 22
Analogous synthetic strategy was also implemented for the preparation of difluoromethyl-substituted
building blocks bearing ester of bromine at C-3 position (Scheme 8).
PCC,
R
R
R
Hal
OH
OH
CH Cl
2
2
OH
O
N
NaHCO3
EtOAc, rt
N
SiO2
N
O
O
1a, 4
23, 57%
24, 68%
25, 78%
26
1
a: R = CO Et, Hal = Cl
2
4
: R = Hal = Br
O
N SF3 CH2Cl2
HO C
2
HO C
2
R
1
. NaOH
MeOH, 0 °C
N
F
F
O
N
F
N
F
O
2. aq HCl
O
F
3
0
(R = CO Et)
2
literature
example
29, 73%
2
2
7, 73%
8, 72% (for 2 steps)
Scheme 8. Preparation of building blocks 28 and 29
The reaction sequence commenced with the reaction of halogenoxymes 1a or 4 with propargyl alcohol
resulted in the hydroxymethyl isoxazoles 23 or 24 in 57% and 68% yield, respectively. Oxidation of 23
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Page 18 of 74
and 24 to the corresponding aldehydes 25 and 26 was more efficient with PCC, while the Parikh –
Doering reagent led to extremely low yields (13% yield for 25). It is interesting to outline that
deoxofluorination of aldehydes 25 and 26 proceeded smoothly, and the products 27 and 28 were
obtained in 73% yield and 72% yield (for two steps), respectively. Mild alkaline hydrolysis of ester 27
using the method applied for the synthesis of 10 provided the carboxylic acid 29 in 73% yield. Building
blocks 28 and 29 were obtained at up to 40 g scale. It should be noted that very similar approach was
described in the literature for the preparation of 30.26
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The aforementioned method was further applied for the preparation of a homologue of 29, i.e. 1,1-
difluoroethyl derivative. The reaction sequence included the cycloaddition of 1a and methyl ethynyl
ketone (resulted in 5-acetylisoxazole-3-carboxylate 31), deoxofluorination to the derivative 32 (1 week,
8
3% yield) and its mild alkaline hydrolysis, which gave 33 in 91% (Scheme 9). Modified Curtius
rearrangement of 33 using DPPA, t-BuOH, Et N gave the corresponding amine 34 in 39% yield after
3
Boc-protection group cleavage.
O
EtO C
2
O
N SF3
EtO C
Cl
2
CH Cl
83%
2
2
O
N
N
NaHCO3
EtOAc, rt
OH
O
EtO C
1a
31
2
78%
F
N
F
O
32
1
. Et N,
t-BuOH
H N
3
HO C
2
2
NaOH
F
F
N
F
2. DPPA, rt
N
MeOH
91%
F
O
O
then 83 °C
39%
3
4
33
Scheme 9. Preparation of 1,1-difluoroethyl carboxylic acid 33 and amine 34
Next, similar strategy was used for the preparation of the F HC-containing analogue of the alkylating
2
agent 12. Thus, the corresponding oxime 35 was transformed to isoxazole 36 by treatment with NCS,
HCl in DMF at 0 °C to rt, followed by addition of propargyl alcohol and NaHCO (Scheme 10). The
3
reaction proceeded for 48 h and led to isoxazole 36 in 41% yield on up to 150 g scale. Subsequent
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oxidation of the chloromethyl derivative 36 to the corresponding aldehyde 37 was performed with PCC
in the presence of SiO in CH Cl at 0 °C to rt. The intermediate 37 was isolated in 68% yield after
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
2
2
distillation and then subjected to the deoxofluorination step providing the target building block 38 in
37% yield.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
. NCS, HCl  1,4-dioxane, Cl
DMF, 0 °C to rt
Cl
Cl
OH
N
N
OH 2.
, NaHCO3
OH
41%
O
36
3
5
PCC, SiO , CH Cl
2,
2
2
6
8%
0 °C to rt, overnight
Cl
N SF3
O
F
N
O
N
O
CH Cl
2
2
O
37
F
37%
3
8
Scheme 10. Synthesis of difluoromethyl-containing alkylating agent 38
Alternatively, aldehydes of the type 17 were transformed into 5-(fluoroalkyl)isoxazoles 39 via
reaction with the Ruppert – Prakash reagent (TMSCF ) (Scheme 11). In this case, N-Boc-protected
3
amino alcohols 39g, 39h and 39k–m were obtained in 44–95% yield. Subsequent oxidation of 39k and
3
9l with the Parikh – Doering reagent led to corresponding ketones isolated as a hydrates 40k and 40l
(45–48% yield), while the Swern reagent led to 40 only in 13% in the most successful case.
DMSO,
TMSCF3,
R
R
R

CsF, THF
Py SO3
OH
OH
OH
CF3
O
N
N
N
0 °C to rt
Et3N, Ar
CH2Cl2
O
O
O
then H O
CF3
2
1
7g and 17h
4495%
39g and 39h
39km
0 °C to rt
40k, 48%
40l, 45%
17km
3
9g: 44%
39h: 49%
R =
R =
BocHN
BocHN
3
9k: 95%
39l: 95%
R =
39m: 75%
BocN
R =
N
N
R =
Boc
Boc
Scheme 11. Preparation of fluorinated isoxazoles 39 and 40
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Moreover, we have tested an approach to the isomers of 40k and 40l from previously described
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5
4
carboxylic acids 41 (Scheme 12). In turn, carboxylic acids 41 were transformed to Weinreb amides 42
90–93% yield), which were used in the aforementioned reaction with TMSCF and CsF in THF,
(
3
resulted in 43 in 72–74% yield.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0

MeNHOMe HCl,
O
O
OMe
BocN
N
OH
CDI, CH Cl
BocN
N
2
2
rt, overnight
N
O
O
4
4
1a, (S)
1b, (R)
42a, (S), 93%
42b, (R), 90%
O
BocN
CF3
1
. TMSCF , CsF, THF
3
4
4
3a, (S), 72%
3b, (R), 74%
N
2. aq work-up
O
Scheme 12. Synthesis of trifluoromethyl ketone 43
It should be noted that in the case of isomeric trifluoromethyl ketones 43a and 43b, no hydrate
formation was observed.
Reaction of chloroximes with aliphatic di- and trifluoromethyl ketones. As it was mentioned
above, fluoroalkyl-substituted isoxazoles can be obtained by reaction of chloroximes and fluorinated
ketones.38–40 The scope of the method studied so far was limited by aryl- or CO Et-substituted
2
chloroximes (Scheme 13).
O
O
O
O
R1
Ar
CF3
Ar
R1
R2
Cl
R1
R2
CF3
F3C
N
Et N or NaH
Et N,
7591%
N
3
3
OH
N
O
CF3
3
2

43%
O
1
2
R = CO Et, aryl; R = OEt, (het)aryl; Ar = Ph, hetaryl
2
Scheme 13. Known reactions of chloroximes and fluorinated ketones
Therefore, we have studied base-mediated reaction of fluorinated -ketoesters 44 and 45 or α-
bromoketones 46 and 47 with chloroximes 1f and 1h–j (Scheme 14). Surprisingly, neither target
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isoxazoles 48 nor isoxazolines 49 were detected in the reaction mixture; instead, 1,4,2-dioxazole
derivatives 50 and 51 were obtained from 44 and 45, respectively, in 39–57% yield. Replacing the
starting ketones 44 and 45 with the corresponding enamines 54 and 55 gave the same products 50 and
51, but with lower yields (36–44%).
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Analogously, 1,4,2-dioxazoles 52j and 53j were synthesized via reaction of -bromoketones 46 and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
7 with chloroxime 1j in 37% and 40% yields, respectively. Although similar transformations leading to
the formation of 1,4,2-dioxazoles were described in the literature recently: they were obtained as minor
products in reactions of chloroximes and -keto esters.38
NMe2
EtO C
2
Rf
R
R
Cl
f
NaHCO3
EWG
54, R = CF
O
3
+
f
N
55, R = CHF
EtOAc,
rt, overnight
N
2
OH
O
Rf
or
O
1
f, 1gl
5053
EWG
Rf
R1
R2
R1
R2
4447
f
4
4, EWG = CO Et, R = CF
2
3
OH
Rf
N
N
Rf
f
45, EWG = CO Et, R = CHF
O
O
2
2
f
46, EWG = Br, R = CF
48
3
49
f
not observed
47, EWG = Br, R = CHF
not observed
2
NHBoc
NHBoc
NHBoc
CO Et
CO Et
CO Et
2
O
2
O
2
O
N
N
N
O
O
O
CHF2
CHF2
CHF2
51f, 39%
51g, 45%
51h, 43%
BocN
BocN
CO Et
Br
O
2
O
N
N
Rf
Rf
O
O
f
f
5
0j, R = CF , 48% (36%)
52j, R = CF , 37%
3
3
f
f
51j, R = CHF , 50% (41%)
53j, R = CHF , 40%
2
2
NBoc
NBoc
CO Et
CO Et
2
O
2
O
N
N
Rf
Rf
O
O
f
f
5
0k, R = CF , 53% (43%)
50l, R = CF , 52% (43%)
3
3
f
f
5
1k, R = CHF , 57% (44%)
51l, R = CHF , 53% (41%)
2
2
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Scheme 14. Formation of 1,4,2-dioxazoles 50–53 (yields from 54 and 55 are given in brackets)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Nevertheless, the product of the type 48, i.e. difluoromethyl isoxazole 48f, could be obtained in low
6
1
yield (13%) by reaction of 45 and 1f in the presence of NiCl 6H O (10% mol.) (Scheme 15). Other
2
2
catalysts like CuSO , Cu(OAc) H O, Cu(OAc) H O – TMEDA, or NiCl 6H O – TMEDA did not
4
2
2
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
improve the reaction outcome.
O
45
CHF2
EtO C
CO Et
Cl
2
BocHN
2
BocHN
N
NaHCO , EtOAc,
N
3
CHF2
OH
O

NiCl 6H O (10% mol),
2
2
1f
48f
rt, overnight, 13%
Scheme 15. Preparation of trisubstituted isoxazole 48f
Synthesis of ABT-418 and ESI-09 analogues. In the above sections, a number of fluorinated
heterocyclic building blocks were obtained at multigram scale. To demonstrate their utility for
medicinal chemistry, several fluorinated isosteric analogues of known biologically active compounds
were prepared. In particular, trifluoromethyl-substituted analogues of ABT-418 – (R)- and (S)-
enantiomers of the compound 56 – were obtained from amines 13k and 13l in 88% and 90% yield,
respectively (Scheme 16).
CH O,
NaBH(OAc)3
2
H N
2
N
N
MeOH, CH Cl2
N
CF3
2
CF3
Cl
O
O
1
1
3k, (S)
3l, (R)
56k, (S), 88%
56l, (R), 90%
Scheme 16. Fluorinated analogues of ABT-418
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In turn, F C-containing analogue 57 of exchange factor directly activated by cAMP (EPAC) inhibitor
3
1
2
ESI-09 was synthesized from ester 3a (Scheme 17). The compound 3a reacted with generated in situ
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
cyanomethyl)lithium to give -ketonitrile 58, which was used in subsequent step without additional
62
purification. F C-ESI 09 57 was obtained from 58 by azo coupling with M–chlorophenyldiazonium in
3
4
6% overall yield.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NC
O
N
1
. MeCN, MeLi,
THF, 78 °C, 0.5 h
EtO
O
2
. 78 to 50 °C, 1 h
CF3
3. HOAc, 0 °C
N
O
CF3
O
3a
58
Cl
Cl
Cl
NH2
NC
NH
N
NC
N
NH
N
1. NaNO2, 1 M HCl,
H O, 0 °C, 5 min
2
O
O

2
. NaOAc 3H O,
2
EtOH, 0 °C
N
O
t-Bu
O
CF3
46% overall yield
ESI-09
57, F C-ESI 09
3
Scheme 17. Fluorinated analogue 57 of EPAC inhibitor ESI-09
Conclusions
Synthetic potential of functionalized halogenoximes for the preparation of fluorinated isoxazole
derivatives has been studied thoroughly. As a result, several different approaches were identified
(Scheme 18). In particular, one-pot metal-free [3+2] cycloaddition of 2-bromo-3,3,3-trifluoropropene
and in situ generated nitrile oxides bearing ester, bromine, chloromethyl, aryl and protected amino
groups is general and regioselective approach to 3-functionalized 5-(trifluoromethyl)isoxazoles (40–
9
5% yield) (method A).
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Base-promoted reaction of halogenoximes and propargilic alcohol was used for the preparation of 3-
substituted 5-((di)fluoromethyl)isoxazoles. Deoxyfluorination of the resulting 5-(hyd-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
roxymethyl)isoxazoles morph-DAST gave the corresponding fluoromethyl derivatives in low yields (6–
31%). Meanwhile, deoxofluorination of the corresponding aldehydes (obtained by oxidation of the
CH OH derivatives with the Parikh – Doering reagent or PCC) was more efficient and gave 5-(difluoro-
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
methyl)isoxazoles in 23–61% overall yield (method B).
More efficient method for the synthesis of 5-fluoromethyl-substituted derivatives included
nucleophilic substitution in the corresponding 5-bromomethyl derivatives (91–98% yield), in turn
prepared by [3+2] cycloaddition of halogenoximes and propargyl bromide (61–71% yield) (method C).
5
-(,,-Trifluoro--hydroxyethyl)isoxazoles were prepared by reaction of isoxazole-5-carbaldehydes
with the Ruppert – Prakash reagent (44–95% yield) (method D). Oxidation of the resulting N-Boc-
protected amino alcohols led to the corresponding 5-(trifluoroacetyl)isoxazoles, which were obtained as
hydrates.
R
R
EWG
Rf
f
EWG
O
R = CF3, CHF2
or
N
N
EWG = Br, CO Et
2
R
Rf
O
O
F
O
N
F
O
E
EWG
Ri
Rf
morph-DAST
B
F3C
Br
OH
R
R
OH
X
N
O
F
N
N
A
O
O
F
R
Ri
F
1.
D
Br
C
TMSCF , CsF
3
R
R = N-Boc-amino acid-
2. KHF , 18-crown-6
F
2
F
derived moiety, CO Et,
R
2
N
F
CH Cl, CH OH, Br, Ar
2
2
O
F
N
O(H)
O
Scheme 18. Summary of methods for the preparation of 5-(fluoroalkyl)isoxazoles developed in this
work
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Experimental part
1
2
3
4
5
6
6
3
The solvents were purified according to the standard procedures. The starting materials 1a–p, 2, 4,
4
4–47, 54 and 55 were purchased from commercial sources. Melting points were measured on an
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
automated melting point system. Analytical TLC was performed using silica gel plates. Column
chromatography was performed using silica gel (230–400 mesh) as the stationary phase. H and 13C
NMR spectra were recorded on a NMR spectrometer at 500 MHz for Protons and 126 MHz for Carbon-
13 or at 400 MHz for protons and 101 MHz for Carbon-13. Chemical shifts are reported in ppm
downfield from TMS as an internal standard. Elemental analyses were performed at the Laboratory of
Organic Analysis, Department of Chemistry, National Taras Shevchenko University of Kyiv. Mass
spectra were recorded on an LCMS instrument (chemical ionization (CI)) and GCMS instrument
(electron impact ionization (EI)). Preparative flash chromatography was performed on chromatograph
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
using 40 g columns. Optical rotations were measured on polarimeter in MeOH (for amine
–1
hydrochlorides) or CHCl (in all other cases) using 1-dm cell; optical rotation values are given in 10
3
2
–1
deg cm g ; concentrations (c) are given in mmol/L, wavelength 589 nm at 20 °C. The enantiomeric
excess and retention time (t ) was determined for major signal by HPLCs. CCDC 1945950 (3h) contain
R
the supplementary crystallographic data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Calculation methods. All calculations were carried out using TURBOMOLE program package
(
versions 6.4).64,65 Geometry optimization and calculation of total energy values were made using DFT
(RI-BP86) approximation with the TZVP basis sets, the implemented into the TURBOMOLE set of
programs polarized Ahlrich’s “triple-zeta” TZV basis sets.66 The structures corresponding to local
minima were re-optimized using Grimme’s RI-B97-D, having a dispersion correction.67–69 For structure
5
a a manual conformational analysis was performed searching the most favorable conformation. The
found total energy variation for the four conformational isomers was quite small (within few tenths
kcal/mol, see the SI for more detail). For locating transition state structures, force constants were
calculated and the standard procedure for location of the transition state structures, implemented into the
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TURBOMOLE set of program, were used. Vibration frequencies and corrections for calculation of
relative energies and relative free Gibbs energies were derived analytically (RI-BP86) or numerically
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(RI-B97-D). For the structures corresponding to local energy minima no imaginary frequencies were
found, whereas for every TS structure only one imaginary frequency was detected. For computing
relative energies, the corresponding corrections on vibrations at 0 K (ZPE) were added to the total
energies. For deriving relative free Gibbs energy values, chemical potential magnitudes calculated at the
standard conditions (pressure: 0.1 MPa, temperature: 298.15 K) with the default scaling coefficient
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(0.9914) were used as corrections for the both DFT methods. Frontier molecular orbitals (FMO) were
5
7
presented graphically using the Chemissian program. Corresponding single-point density matrices and
NBO atomic charges58,59 were derived for the isolated molecules of 1,3-dipoles and dipolarophile using
the GAUSSIAN-09 set of programs.70
General procedure for the preparation of isoxazoles 3a–o.
The corresponding halogenoxime 1a–o (40.2 mmol, 1 eq) was dissolved in EtOAc (100 mL, 0.4 M
solution of 1a–o) (NOTE: in the case of 1j, EtOAc – THF (100 mL, 1:1, v/v) was used), and 2-bromo-
3
,3,3-trifluoro-1-propene (2, 21.1 g, 121 mmol, 3 eq) and NaHCO (11.1 g, 133 mmol, 3.3 eq) were
3
added to the vigorously stirred homogeneous solution at rt. The resulting mixture was stirred overnight.
1
The completion of the reaction was monitored by H NMR spectroscopy. Then, the resulting mixture
was filtered through a plug of silica gel and evaporated in vacuo.
53
Ethyl 5-(trifluoromethyl)isoxazole-3-carboxylate (3a). The compound was purified by distillation
in vacuo. Yield 5.81 g (69%, can be scaled up to 95.2 g by using 1a (100 g, 0.660 mol) and 2 (346 g,
1
1
.98 mol)); colorless oil; bp 39–40 °C / 8.5 mmHg. H NMR (400 MHz, DMSO-d ) δ 7.91 (d, J = 1.1
6
1
3
1
Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H). C{ H} NMR (101 MHz, DMSO-d ) δ
6
1
9
1
159.1 (q, J = 42.7 Hz), 158.3, 117.8 (q, J = 270 Hz), 108.0 (q, J = 2.3 Hz), 62.9, 14.1. F{ H} NMR
+
(
376 MHz, DMSO-d ) δ –64.0. LC/MS (CI): m/z = 210 [M+H] . Anal. Calcd. for C H F NO : C, 40.20;
6
7
6
3
3
H, 2.89; N, 6.70. Found: C, 40.59; H, 3.28; N, 6.84.
3
-Phenyl-5-(trifluoromethyl)isoxazole (3b).71,72 The compound was purified by distillation in vacuo.
1
Yield 3.77 g (44%); colorless powder; mp 76–78 °C; sublimation 55–57 °C / 0.8 mmHg. H NMR (400
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The Journal of Organic Chemistry
1
3
1
MHz, DMSO-d ) δ 8.07 (s, 1H), 7.99 – 7.93 (m, 2H), 7.60 – 7.53 (m, 3H). C{ H} NMR (101 MHz,
6
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
DMSO-d ) δ 163.2, 157.9 (q, J = 41.7 Hz), 131.6, 129.7, 127.4, 127.2, 118.3 (q, J = 270 Hz), 105.9 (d, J
6
1
9
1
+
+
=
2.4 Hz). F{ H} NMR (376 MHz, DMSO-d ) δ –63.9. GC/MS (EI): m/z = 77 [Ph] , 144 [M–CF ] ,
6 3
+
+
194 [M–F] , 213 [M] .Anal. Calcd. for C H F NO: C, 56.35; H, 2.84; N, 6.57. Found: C, 56.57; H,
1
0
6 3
2
.60; N, 6.29.
-(4-Methoxyphenyl)-5-(trifluoromethyl)isoxazole (3c). The compound was purified by column
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
chromatography on silica gel (40 g RediSep column; run length: 89.2 CV; flow rate: 60 mL / min; rack:
16 mm  150 mm tubes) using hexanes – t-BuOMe (3:2) as eluent. Yield 7.23 g (74%); beige powder;
1
mp 72–75 °C. H NMR (400 MHz, DMSO-d ) δ 8.01 (s, 1H), 7.95 – 7.83 (m, 2H), 7.17 – 7.07 (m, 2H),
6
1
3
1
3
.83 (s, 3H). C{ H} NMR (101 MHz, DMSO-d ) δ 162.7, 161.9, 157.6 (q, J = 41.6 Hz), 129.0, 119.5,
6
1
9
1
1
18.4 (q, J = 270 Hz), 115.1, 105.6, 105.6, 55.7. F{ H} NMR (376 MHz, DMSO-d ) δ –63.9. GC/MS
6
+
+
+
+
+
(EI): m/z = 76 [C H ] , 107 [C H OMe] , 174 [M–CF ] , 224 [M–F] , 243 [M] . Anal. Calcd. for
6
4
6
4
3
C H F NO : C, 54.33; H, 3.32; N, 5.76. Found: C, 54.25; H, 2.99; N, 5.81.
1
1
8
3
2
3
-(4-Fluorophenyl)-5-(trifluoromethyl)isoxazole (3d). The compound was purified by column
chromatography on silica gel (40 g RediSep column; run length: 63.0 CV; flow rate: 60 mL / min; rack:
16 mm  150 mm tubes) using hexanes – t-BuOMe (7:3) as eluent. Yield 6.88 g (73%); colorless
1
powder; mp 45–47 °C. H NMR (400 MHz, DMSO-d ) δ 8.07 (s, 1H), 8.01 (dd, J = 8.9, 5.3 Hz, 2H),
6
1
3
1
7
.40 (t, J = 8.9 Hz, 2H). C{ H} NMR (101 MHz, DMSO-d ) δ 164.2 (d, J = 249 Hz), 162.2, 157.9 (q,
6
J = 41.8 Hz), 129.8 (d, J = 8.9 Hz), 123.7 (d, J = 3.3 Hz), 118.3 (q, J = 270 Hz), 116.7 (d, J = 22.1 Hz),
1
9
1
105.7 (q, J = 2.3 Hz). F{ H} NMR (376 MHz, DMSO-d ) δ –64.1, –109.9 (tt, J = 8.9, 5.3 Hz). GC/MS
6
+
+
+
(EI): m/z = 162 [M–CF ] , 212 [M–F] , 231 [M] . Anal. Calcd. for C H F NO: C, 51.96; H, 2.18; N,
3
10
5 4
6
.06. Found: C, 51.97; H, 2.31; N, 6.01.
3
-(Thiophen-2-yl)-5-(trifluoromethyl)isoxazole (3e). The compound was purified by column
chromatography on silica gel (40 g RediSep column; run length: 74.0 CV; flow rate: 60 mL / min; rack:
16 mm  150 mm tubes) using hexanes – CHCl (4:1) as eluent. Yield 3.52 g (40%); colorless powder;
3
1
mp 112–113 °C; sublimation 50–52 °C / 0.4 mmHg. H NMR (400 MHz, DMSO-d ) δ 8.04 (s, 1H),
6
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3
1
7
.89 – 7.82 (m, 2H), 7.27 (dd, J = 5.1, 3.7 Hz, 1H). C{ H} NMR (126 MHz, DMSO-d ) δ 158.7, 157.6
6
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
9
1
(
q, J = 41.5 Hz), 131.4, 130.7, 128.8, 128.1, 118.2 (q, J = 271 Hz), 105.9 (d, J = 2.4 Hz). F{ H} NMR
+
(
376 MHz, DMSO-d ) δ –63.8. LC/MS (CI): m/z = 220 [M+H] . Anal. Calcd. for C H F NOS: C,
6
8
4 3
43.84; H, 1.84; N, 6.39; S, 14.63. Found: C, 43.56; H, 1.65; N, 6.09; S, 14.46.
tert-Butyl ((5-(trifluoromethyl)isoxazol-3-yl)methyl)carbamate (3f). The compound was purified
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
by column chromatography on silica gel using hexanes – CHCl (4:1) as eluent. Yield 9.52 g (89%);
3
colorless powder; mp 62–64 °C. In the case of using 1f (160 g, 0.767 mol), the reaction was performed
1
with 2 (335 g, 1.92 mol) and NaHCO (128 g, 1.53 mol), which gave 148 g (73%) of 3f. H NMR (400
3
1
3
1
MHz, DMSO-d ) δ 7.51 (t, J = 5.9 Hz, 1H), 7.24 (s, 1H), 4.27 (d, J = 5.6 Hz, 2H), 1.39 (s, 9H). C{ H}
6
NMR (126 MHz, DMSO-d ) δ 163.6, 156.8 (q, J = 41.6 Hz), 155.7, 117.9 (q, J = 270 Hz), 106.2, 78.5,
6
5.6, 28.1. 19F{ H} NMR (376 MHz, DMSO-d ): δ –63.9. GC/MS (EI): m/z = 57 [t-Bu] , 150 [M–
1
+
3
6
+
+
+
+
NHCO t-Bu] , 166 [M-CO –H C=C(CH ) ] , 193 [M–Ot-Bu] , 210 [M–H C=C(CH ) ] . Anal. Calcd.
2
2
2
3 2
2
3 2
for C H F N O : C, 45.12; H, 4.92; N, 10.52. Found: C, 45.22; H, 4.69; N, 10.89.
1
0
13
3
2
3
(S)-tert-Butyl (1-(5-(trifluoromethyl)isoxazol-3-yl)ethyl)carbamate (3g). The compound was
purified by column chromatography on silica gel (125 g RediSep column; run length: 14.2 CV; flow
rate: 100 mL / min; rack: 16 mm  150 mm tubes) using hexanes – t-BuOMe (7:3) as eluent. Yield 8.11
g (72%); colorless powder; mp 86–88 °C. [α]20 = –55.3 (с = 35.7, CHCl ), 98% ee, t = 9.53 min. H
1
D
3
R
NMR (500 MHz, DMSO-d ) δ 7.52 (d, J = 6.6 Hz, 1H), 7.28 (s, 1H), 4.89 – 4.78 (m, 1H), 1.40 (s, 3H),
6
1
3
1
1
2
=
.38 (s, 9H). C{ H} NMR (126 MHz, DMSO-d ) δ 167.4, 156.7 (q, J = 41.6 Hz), 154.9, 117.9 (q, J =
6
1
9
1
70 Hz), 105.4, 78.4, 42.9, 28.0, 19.7. F{ H} NMR (376 MHz, DMSO-d ): δ –63.1. GC/MS (EI): m/z
6
+
+
+
+
57 [t-Bu] , 164 [M–NHCO t-Bu] , 180 [M–CO –H C=C(CH ) ] , 207 [M–Ot-Bu] , 224 [M–
2
2
2
3 2
+
+
H C=C(CH ) ] , 265 [M–CH ] . Anal. Calcd. for C H F N O : C, 47.14; H, 5.40; N, 10.00. Found: C,
2
3 2
3
11 15
3
2
3
4
7.44; H, 5.57; N, 10.27.
R)-tert-Butyl (1-(5-(trifluoromethyl)isoxazol-3-yl)ethyl)carbamate (3h). The compound was
(
purified by column chromatography on silica gel using hexanes – t-BuOMe (7:3) as eluent. Yield 8.56 g
(76%); colorless powder; mp 86–88 °C. [α]20 = +53.2 (с = 35.7, CHCl ), 96% ee, t = 10.4 min. The
D
3
R
+
spectral data are analogous to that of S-isomer 3g. LC/MS (CI): m/z = 165 [M–NHCO t-Bu+H] , 181
2
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The Journal of Organic Chemistry
+
+
+
[
M–CO –H C=C(CH ) ] , 208 [M–Ot-Bu+H] , 225 [M–H C=C(CH ) +H] . Anal. Calcd. for
2
2
3 2
2
3 2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
C H F N O : C, 47.14; H, 5.40; N, 10.00. Found: C, 46.85; H, 5.64; N, 10.11.
1
1
15
3
2
3
tert-Butyl (2-(5-(trifluoromethyl)isoxazol-3-yl)propan-2-yl)carbamate (3i). The compound was
purified by HPLC (SunFire C Column, 100 Å, 3.5 µm, 4.6 mm  150 mm, 0–9.5 min; H O – MeCN;
1
8
2
flow rate 30mL / min) or by column chromatography on silica gel using hexanes – t-BuOMe (7:3) as
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
eluent. Yield 10.1 g (85%); colorless powder; mp 79–81 °C. H NMR (400 MHz, DMSO-d ) δ 7.46 –
6
1
7
.33 (m, 1H), 7.30 (s, 1H), 1.53 (s, 6H), 1.32 (s, 9H). H NMR (400 MHz, CDCl ) δ 6.68 (s, 1H), 4.96
3
1
3
1
(s, 1H), 1.66 (s, 6H), 1.37 (s, 9H). C{ H} NMR (126 MHz, CDCl ) δ 169.8, 158.3 (q, J = 42.3 Hz),
3
19
1
1
54.3, 117.9 (q, J = 270 Hz), 103.8, 80.1, 51.4, 28.2, 27.9. F{ H} NMR (470 MHz, CDCl ) δ –64.2.
3
+
+
+
+
GC/MS (EI): m/z = 57 [t-Bu] , 178 [M–NHCO t-Bu] , 194 [M–CO –H C=C(CH ) ] , 221 [M–Ot-Bu] ,
2
2
2
3 2
+
2
38 [M–H C=C(CH ) ] . Anal. Calcd. for C H F N O : C, 48.98; H, 5.82; N, 9.52. Found: C, 49.01;
2 3 2 12 17 3 2 3
H, 6.07; N, 9.52.
tert-Butyl 3-(5-(trifluoromethyl)isoxazol-3-yl)azetidine-1-carboxylate (3j). The compound was
purified by column chromatography on silica gel (80 g RediSep column; run length: 20.7 CV; flow rate:
6
0 mL / min; rack: 16 mm  150 mm tubes) using hexanes – t-BuOMe (7:3) as eluent. Yield 4.93 g
(42% if the reaction was performed in EtOAc) or 9.51 g (81% if the reaction was performed in EtOAc –
1
THF); colorless powder; mp 57–58 °C. H NMR (400 MHz, DMSO-d ) δ 7.64 (s, 1H), 4.23 (d, J = 6.8
6
1
3
1
Hz, 2H), 4.04 – 3.93 (m, 3H), 1.39 (s, 9H). C{ H} NMR (101 MHz, DMSO-d ) δ 166.0, 157.5 (d, J =
6
1
9
1
4
1.5 Hz), 155.9, 117.0 (q, J = 276 Hz), 106.9, 54.1, 28.5, 25.3. F{ H} NMR (376 MHz, DMSO-d ): δ
6
+
+
+
–63.7. GC/MS (EI): m/z = 57 [t-Bu] , 192 [M–CO –H C=C(CH ) ] , 219 [M–Ot-Bu] , 236 [M–
2
2
3 2
+
H C=C(CH ) ] . Anal. Calcd. for C H F N O : C, 49.32; H, 5.17; N, 9.59. Found: C, 49.62; H, 5.43;
2
3 2
12 15
3
2
3
N, 9.46.
(S)-tert-Butyl 2-(5-(trifluoromethyl)isoxazol-3-yl)pyrrolidine-1-carboxylate (3k). The compound;
purified by column chromatography on silica gel (125 g RediSep column; run length: 18.2 CV; flow
rate: 100 mL / min; rack: 16 mm  150 mm tubes) using hexanes – t-BuOMe (3:2) as eluent; existed as
ca. 5:4 mixture of rotamers. Yield 11.6 g (94%); white crystals; mp 55–58 °C; bp 82–84 °C / 1 mmHg.
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