Regioselective Synthesis of Functionalized 3- or 5-Fluoroalkyl Isoxazoles and Pyrazoles from Fluoroalkyl Ynones and Binucleophiles

Article abstract of DOI:10.1021/acs.joc.9b02258

A facile synthetic route toward either 3- or 5-fluoroalkyl-substituted isoxazoles or pyrazoles containing an additional functionalization site was developed and applied on a multigram scale. The elaborated approach extends the scope of fluoroalkyl substituents for introduction into the heterocyclic moiety, and uses convenient transformations of the side chain for incorporation of fluoroalkyl-substituted azoles into the structures of biologically active molecules. The utility of the obtained building blocks for isosteric replacement of alkyl-substituted isoxazole and pyrazole was shown by the synthesis of fluorinated Isocarboxazid and Mepiprazole analogues.

Full text of DOI:10.1021/acs.joc.9b02258

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Article
Regioselective Synthesis of Functionalized 3- or 5-Fluoroalkyl
Isoxazoles and Pyrazoles from Fluoroalkyl Ynones and Binucleophiles
Bohdan A. Chalyk, Andrii Khutorianskyi, Andrii Lysenko, Yulia Fil, Yuliya O. Kuchkovska, Konstantin
S. Gavrilenko, Iulia Bakanovych, Yurii S. Moroz, Alina O. Gorlova, and Oleksandr O. Grygorenko
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02258 • Publication Date (Web): 29 Oct 2019
Downloaded from pubs.acs.org on November 3, 2019
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Regioselective Synthesis of Functionalized 3- or 5-
Fluoroalkyl Isoxazoles and Pyrazoles from
Fluoroalkyl Ynones and Binucleophiles
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Bohdan A. Chalyk,a,d Andrii Khutorianskyi, a,b Andrii Lysenko,a,b Yulia Fil,a,b Yuliya O.
Kuchkovska, a,b Konstantin S. Gavrilenko,a,b Iulia Bakanovych,a,b Yurii S. Moroz,b,c Alina
a,d
a,b
O. Gorlova, and Oleksandr O. Grygorenko *
a
Enamine Ltd. (www.enamine.net) Chervonotkatska Street 78, Kyiv 02094, Ukraine
b
Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01601,
Ukraine
c
Chemspace, Ilukstes iela 38-5, Riga, LV-1082, Latvia
d
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska
Street 5, Kyiv 02660, Ukraine
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*E-mail: gregor@univ.kiev.ua
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KEYWORDS: Isoxazole; pyrazole; organofluorine compounds; cyclization; ynone
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ABSTRACT. A facile synthetic route towards either 3- or 5-fluoroalkyl-substituted
isoxazoles or pyrazoles containing an additional functionalization site was developed
and applied on a multigram scale. The elaborated approach extends the scope of
fluoroalkyl substituents for introduction into the heterocyclic moiety, and uses
convenient transformations of the side chain for incorporation of fluoroalkyl substituted
azoles into the structures of biologically active molecules. The utility of the obtained
building blocks for isosteric replacement of alkyl-substituted isoxazole and pyrazole was
shown by the synthesis of fluorinated Isocarboxazid and Mepiprazole analogues.
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INTRODUCTION
Importance of isoxazoles and pyrazoles for discovery of new therapeutics and
agricultural ingredients was highlighted in a number of reviews.1–6 Because of
advantageous capability of fluorinated substituents to modulate drug-related
properties,7–13 their incorporation to azoles provide promising opportunity for drug
discovery. For example, substitution of tert-butyl group at isoxazole ring of BRAFV600E
inhibitor 1 to its fluorinated analogue in 3 prevented the metabolic oxidation of 1 to
significantly less active derivative 2 (Figure 1, A)14 and led to the discovery of clinical
candidate Agerafenib. In addition to that, the fluoroalkylated pyrazole moiety is present
in structures of marketed anti-inflammatory drug Celecoxib,15 veterinary drugs
Deracoxib16 and Mavacoxib17 (also from coxib series, Figure 1, B), as well as in
structures of marketed agrochemicals Bixafen, Sedaxane, Isopyrazam, and
Fluxapyroxad.5
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HO
F
(
A)
F
O
F
O
R
R
1
2
3
O
N
BRAFV600E K (nM)
71
49
14
82
78
O
d
N
N
N
O
N
H
H
A375 pMEK IC50 (nM) 121
649
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Agerafenib (3)
A375 Proliferation
IC50 (nM)
328
> 15 000
R2
(
B)
Celecoxib
Deracoxib
Mavacoxib
R3
R1
F
F
R1
F
CH3
H
H
F
N
R2
OCH3
F
N
O
R3
F
H
S
NH2
O
Figure 1. (A) Influence of fluoroalkyl substituent on the potency of Agerafenib and its
analogues. (B) Examples of marketed drugs containing fluoroalkyl-substituted pyrazole
moiety.
Among the previously reported approaches to 3- and 5-fluoroalkyl-substituted
isoxazoles, the most important are cycloaddition of nitrile oxides with either 1-
substituted vinyl bromides or monosubstituted alkynes,18–22 and reaction of fluoroalkyl-
23–26
substituted diketones and their synthetic equivalents with NH OH.
However, both
2
these methods were studied for a limited scope of substrates and in several cases were
accompanied with regioselectivity issues. In contrast to isoxazoles, the synthetic
methods towards fluoroalkyl-substituted pyrazoles are more comprehensively studied.27
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Recently, synthesis of 5-CF - and 3-CF -pyrazoles 4a and 5a by cyclocondensation of
3
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(hetero)aryl- and alkyl-substituted 1,1,1-trifluorobut-3-yn-2-ones 6 with mono- and
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unsubstituted hydrazines (Scheme 1) was reported in a series of works by
Nenajdenko`s and Hseih`s research groups.28–32 Surprisingly, similar reaction of 6 with
NH OH leading to the formation of fluoroalkyl-substituted isoxazoles 4b and 5b was
2
mentioned just in two patents33,34 and was studied only in a single article by Linderman
and Kirillos in 1989.35 In their work, the synthesis of only 3- and 5-octyl-substituted
isoxazoles bearing either CF or CHF group was achieved. Yet, the suggested
3
2
cyclization conditions (either NaOMe in MeOH for preparation of 7b or AcOH with cat.
HCl for 8b) would be hardly adaptable for the preparation of functionalized derivatives.
Additionally, increased stability of fluoroalkyl-substituted hemiketal moiety in
hydroxypyrazolines 7a and hydroxyisoxazolines 7b was previously
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NH XH
OH 1,4-addition
NH XH
1,2-addition
X
2
2
O
X
N
R1
RF
R1
N
RF
RF
(a) X = NH/NR2
RF
(a) X = NH/NR2
(b) X = O
RF
8a,b
N X
X N
a,b
R1
R1
R1
(b) X = O
4
7a,b
6
5a,b
1
2
Previous works:
This work:
RF = CHF2, CF3
R = alkyl, aryl, heteroaryl
R = aryl, heteroaryl, Ts, Boc, Et, t-Bu
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RF
FG
RF
FG
RF
FG
RF
FG
O N
N O
N
NH
11
(CH ) CHO
N
N
9
10
12
RF = CHF2
C2F5
CHFBr
FG = (CH ) OH
2 n
(CH ) N
2 n-1
2 n 3
CF3
(CH2)n-1CO2H (CH2)nCl
(CH2)nNH2
CF Me CF Br
2
2
and other derivatives; n = 12
Scheme 1. Synthesis of 3- and 5-fluoroalkyl substituted pyrazoles and isoxazoles from
ynones 6, and compounds 9–12 attempted in this work.
reported to complicate the dehydration step;36–38 therefore, revision of the dehydration
conditions was necessary.
In this report, we have elaborated an efficient approach towards the synthesis of
azoles 9–12 (Scheme 1) and applied it on a multigram scale. The reaction sequence
was designed to meet three main objectives. First, we aimed at the method that could
extend the diversity of fluoroalkyl substituents and use commercially available materials
as fluorine-containing precursors. Second, the reaction sequence should result in
azoles containing various functional groups, which may allow the incorporation of the
final building blocks to the structures of more complex biologically active molecules by
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commonly used chemical transformations. The third goal was the preparation of all
target products from common starting reagents as single regioisomers. In addition to
that, the utility of the obtained compounds for isosteric replacement of 5-
methylisoxazole and 5-methyl-1H-pyrazole moieties was demonstrated by synthesis of
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fluorinated Isocarboxazid and Mepiprazole analogues.
RESULTS AND DISCUSSION
Synthesis of starting ynones. Our work commenced with synthesis of a series of
ynones 13 (Scheme 2). In order to provide diversity of the fluoroalkyl substituents, the
reaction of commercially available fluorinated acetic acid esters 14 with deprotonated
terminal alkynes 15 was carried out. A selection of alkynes 15 containing TBS-protected
alcohol moiety was envisaged to ensure the stability of the side chain group towards
heterocyclization reaction conditions and its further mild removal. Thus, the resulting
azole with a free OH group can be further transformed to other functionalized
derivatives by commonly used reactions.
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O
1
. BuLi, THF, 78 °C
R1
RF
2. R CO Et, BF ·Et O
F
2
3
2
R1
1
5
14
13
1
15a, R = CH OTBS
2
1
15b, R = (CH ) OTBS
2
2
1
1
5c, R = CH(CH )OTBS
3
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O
O
F2HC
RF
OTBS
OTBS
1
3g, 87%
1
3a, RF = CHF2
13b, RF = CF3
80%
81%
83%
58%
76%
69%
O
1
1
1
1
3c, RF = CF CH3
2
F2HC
OTBS
3d, RF = C2F5
3e, RF = CHFBr
3f, RF = CF Br
13h, 81%
2
Scheme 2. Preparation of ynones 13.
To prepare ynones 13, reaction of esters 14 and lithium acetylenides (obtained in situ
from 15 and n-BuLi) was envisaged. It was found that at these conditions, complex
mixtures were formed. Nonetheless, these side reactions could be suppressed when
3
2,41
BF ·OEt was introduced into the reaction mixture
immediately after the addition of
3
2
esters 14, and the target compounds 13a–h were obtained in 58–87% yield. Importantly,
when BF ·OEt was introduced to the reaction mixture more than one hour after the
3
2
addition of 14, a significant yield decrease was observed for the products 13.
Synthesis of 5-fluoroalkyl isoxazoles. Next, the 1,4-addition of NH OH to ynone 13a
2
was studied in a series of solvents on 0.5 g scale (Table 1). When ynone 13a was
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mixed with 1.2 eq of NH OH·HCl, no conversion of the starting material was observed in
2
any solvent system mentioned in Table 1. Therefore, addition of 1.2 eq of NaHCO was
3
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essential for the reaction to proceed. Although alcohol and alcohol – H O solvent
2
systems are commonly used for the synthesis of non-fluorinated hydroxyisoxazolines,42
in the case of the ynone 13a, formation of a mixture containing 16a–20a was indicated
by H NMR and 19F NMR at both rt and 0 °C. Although switching to polar aprotic
1
solvents such as DMF and CH CN increased the yield of
3
Table 1. Optimization of reaction conditions for 16a synthesis.
F2HC
CHF2
O
OH
O
+
N
N
OTBS
16a
OTBS
O
CHF2
17a
NH OH·HCl
2
OH
N
NaHCO3
solvent
CHF2
N
CHF2
TBSO
+
+
13
O
OR1
OTBS
8a
1
1
19a, R = TBS
1
20a, R = H
1
6a yield,
% a,b
entry
1
solvent
T-re
rt
MeOH–H O
2
23
(1 : 1)
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MeOH–H O
2
2
0 °C
51
(1 : 1)
3
4
5
DMF
0 °C
0 °C
0 °C
74
77
91
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CH CN
3
CH Cl
2
2
CH Cl –H O
2
2
2
6
7
0 °C
97
(10 : 1)
THF
0 °C
99
a
b
1
19
Reaction yields were measured by H NMR and F NMR;
The reactions were carried out on 0.5 g scale.
1
6a up to 74%, formation of the aforementioned byproducts was not eliminated
completely. Instead, using nonpolar CH Cl gave 16a as a single product with 91%
2
2
yield. In order to facilitate the heterogeneous reaction of NaHCO with NH OH·HCl in
3
2
CH Cl , the two-phase CH Cl –H O (10:1) system was used under vigorous stirring; this
2
2
2
2
2
increased the product yield to 97%. Finally, the best result was achieved when a
solution of ynone 16a in THF was treated with a solution of pre-synthesized NH OH
2
(
from NH OH·HCl and NaHCO ) in a minimal amount of H O (99% on 0.5 g scale and
2
3
2
8
4% on 200 g scale). Formation of hydroxyisoxazolines 16 instead of isoxazoles 17 in
the reaction of ynones 13 with NH OH can be explained by modest aromaticity of
2
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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
4
3
isoxazoles along with electron-withdrawing effect of the fluoroalkyl substituents which
stabilize hemiketals.38
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
Table 2. Optimization of reaction conditions for 17a synthesis.
F2HC
N
CHF2
O
CHF2
O
OH
conditions
O
+
N
N
OTBS
6a
OTBS
17a
OH
1
21a
+
other byproducts
17a
yield,a
16a
21a
entry
1
conditions
CF CO) O (1.2 equiv), py (2.5 equiv),
conversion,a,b
%
%
yield, %
a
(
3
2
80
100
38
33
15
0
14
12
0
CH Cl , –10 °C
2
2
SOCl (1.2 equiv), NEt (3 equiv),
2
3
2
3
CH Cl ,
2
2
–
10 °C
TsCl (1.1 equiv), py (2 equiv), CH Cl , 0
2
2
°C
4
5
6
7
8
Ac O (1.2 equiv), CH Cl , rt
30
100
0
21
0
0
0
2
2
2
H SO (cat), MeOH, rt
2
4
Cationite KU-2-8 (20 wt. %), PhH, reflux
HBr (33 wt. % in AcOH), rt
0
0
100
100
0
61
0
KOH (3 equiv), EtOH, reflux
0
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Page 13 of 81
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9
9
CDI (1.1 equiv), CH CN, reflux
100
100
100
84
91
0
0
0
3
10
CDI (1.1 equiv), CH CN, rt
3
11
CDI (1.1 equiv), CH Cl , rt
97c
2
2
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
a
1
The conversion of 16a and yields of isoxazoles 17a and 21a were measured by H
19
NMR and F NMR.
b
The experiments were carried out on 0.5 g scale.
c
9
4% yield was achieved on 185 g scale.
Further dehydration of hydroxyisoxazolines 16 to isoxazoles 17 required careful
optimization of the reaction conditions, which were performed with 0.5 g of 16a as a
model substrate (Table 2). The evaluated methods included acylation and sulfonylation
of alcohols followed by β-elimination (entries 1–4), as well as dehydration under acidic
(entries 5–7) and basic (entry 8) conditions. In more detail, the unsuccessful
experiments with both catalytic amounts of H SO (entry 5) and 3 equiv of KOH (entry
2
4
8
) resulted in the formation of mixtures of unidentified byproducts, whereas refluxing
with strong cationite KU-2-8 (entry 6) had no effect on the starting reagent 16a.
Reaction of 16a with TsCl (entry 3) gave only tosylated product and was not followed by
further elimination.
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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
Although some of the studied methods allowed the synthesis of compounds 17a and
1a either as single products or as a mixture, still all of them were inefficient for the
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
multigram preparation of the target product 17a. Thus, we have elaborated a new
method for dehydration of hydroxyisoxazolines 16 with carbonyldiimidazole (CDI), which
provided mild conditions for this transformation (entries 9–11). The best yield (97%) was
achieved using 1.1 eq of CDI in CH Cl at rt (entry 11). Moreover, the scale-up of this
2
2
procedure to 185 g of 16a resulted in 94% yield of the target product 17a. A proposed
mechanism of this reaction is given in Scheme 3.
O
N
N
O
N
N
OH
RF
O
CDI
HN
N
R1
N
R1
O
N
RF
O
N
N
16
HN
HN
N
HN
HN
NH
N

O
RF
H
N
R1
O
N
O
NH
N
R1
NH

O RF
17

CO2
Scheme 3. Proposed mechanism for the dehydration of hydroxyisoxazolines 16 with
CDI.
Table 3. Synthesis of the compounds 16, 17 and 21.
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8
9
O
OH
R1
R1
RF
NH OH
CDI
2
RF
RF
N O
R1
THF
N O
CH2Cl2
13
16
17
R1
KHF2
MeOHH O
HO
RF
HO
RF
RF
HO
RF
N
N
N
N
O
O
2
O
O
(
9 : 1)
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
17
21af
21g
21h
entry
R1
RF
16 (yield, %)
16a (84)
16b (83)
16c (77)
16d (75)
16e (85)
16f (73)
17 (yield, %) 21 (yield, %)
21a (91)a
1
2
3
4
5
6
7
8
CH OTBS
CHF2
CF3
17a (94)
2
CH OTBS
17b (91)
21b (70)a
2
17cb
21c (74)c
CH OTBS
CF CH
2
2
3
CH OTBS
C2F5
17d (89)
17e (85)
17f (83)
17g (75)
17h (83)
21d (87)a
21e (81)
21f (-)
2
CH OTBS
CHFBr
2
CH OTBS
CF Br
2
2
(CH ) OTBS
CHF2
CHF2
16g (59)
16h (82)
21g (91)
21h (92)
2
2
CH(CH3)
OTBS
a
The three-step reaction sequence was carried out on 179–250 g scale.
The compound was used in the next step without additional purification.
The overall yield for two steps is given.
b
c
The optimized protocols for both steps were applied to ynones 13b–h. As a result,
hydroxyisoxazolines 16a–h were obtained in 59–85% yield on a multigram scale and
converted to isoxazoles 17a–h in 75–94% yield (Table 3). Further removal of the silyl
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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
group using KHF led to alcohols 21a–e,g,h in 70–92% yield. The product 21f could not
2
be isolated in pure form due to its limited stability. In the case of alkyne 13g, the
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
reaction with NH OH led to a mixture of cyclization product 16g and corresponding
2
oxime in ca. 2:1 ratio, presumably due to less electron-withdrawing effect of the TBS-
protected hydroxyethyl group as compared to CH OTBS. Thus, compound 16g was
2
obtained in 59% yield after separation by column chromatography.
Synthesis of 3-fluoroalkyl-substituted isoxazoles. The synthetic route to regioisomeric
3-fluoroalkyl-substituted isoxazoles relied on metal-catalyzed 1,2-addition of NH OH to
2
ynones 13, followed by cyclization of the intermediate oxime. Previous reports
discussing analogous cyclization of non-fluorinated ynones through methyl- or benzyl-
O-substituted and O-non-substituted oxime intermediates used Au(III),44–48 Au(I),48
Ag(I),46,48 Cu(II),48 Cu(I),49,50 Pd(II),51 and Fe(III)52 catalysts. Therefore, salts of these
transition metals (except for Au) were screened first for the reaction of 13a with NH OH
2
in THF (Table 4, entries 1–9). Generally, for these (entries 1–9) and other (entries 10–
19) catalysts the reaction resulted in formation of oxime 18a, TBS-deprotected
derivative 20a and other byproducts along with the target isoxazole 19a. In the case of
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8
9
Pd(OAc) , ynone 13a was fully converted to a mixture of unidentified products.
2
Conversely, the use of Ag(I) salts (entries 2–5) resulted in up to 67% yield of the target
product 19a. However, the high 33% proportion of the starting material along with
byproducts was unsatisfactory. The better results were obtained in Cu(I) and Cu(II)
catalyst series (entries 6–9). In particular, the cumulative yield of 19a and 20a obtained
under CuI catalysis was 82%.
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
Although other transition metal catalysts also appeared to be moderately effective for
oxime 18a cyclization (up to 80% yield, entries 10–16), they did not surpass the results
observed for Cu-based catalysts. Hence, the selection of the solvent and catalyst ratio
was additionally studied using CuI. When the reaction was carried out in dioxane or
dimethoxyethane, the yields of the products 19a and 20a were slightly lower as
compared to the experiment carried out in THF, whereas the ratio of byproducts was
increased. Optimization of the amount of CuI showed that usage of more than 0.10
equiv did not influence the reaction yield, while the usage of less than
Table 4. Catalyst screening for the preparation of 19a.
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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
O
CHF2
1
N
CHF2
+
CHF2
N
HO
) NH OH·HCl
2
catalyst (0.1 eq)
O
OR1
2) NaHCO3
TBSO
TBSO
1
3a
THF
18a
1
1
9a, R = TBS
1
2
0a, R = H
+
other byproducts
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
entry
catalyst
19a
20a
yield,a
%
yield,a
%
1
2
Pd(OAc)2
0
0
9
AgBF4
20
23
25
67
40
68
74
75
30
48
56
73
75
76
3
AgNO3
AgOAc
11
8
4
5
AgOSO CF
0
2
3
6
CuCl
28
4
7
CuBr2
8
CuSO ·5H O
6
4
2
9
CuI
7
10
Pd(PPh3)4
NiCl ·6H O
0
11
12
13
14
0
2
2
Rh Cl (COD)
0
2
2
2
Co (CO)
0
2
8
CeCl3
0
15
Zn(CN)2
0
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7
8
9
1
6
7
FeSO4
80
87
89
90
0
0
0
0
1
Cu O
2
18 Cu(OAc) ·H O
2
2
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
19
CuCN
a
Yield was determined from H NMR and 19F NMR spectra. The experiments were
1
carried out on 0.5 g scale.
0
.10 equiv slowed the reaction and facilitated formation of undesirable byproducts.
Further survey of other Cu-based catalysts allowed achieving even higher yields using
Cu O, Cu(OAc) ·H O, and CuCN. These catalysts led to the product 19a in 87–90%
2
2
2
yield (entries 17–19) in a mixture with ca. 10% of oxime 18a.
After ynones 13 were subjected to the reaction with NH OH under Cu(I)-catalysis, the
2
crude products 19 were further deprotected with KHF to give alcohols 20 (63–93%
2
yield for 2 steps, Scheme 4), which were purified by distillation in vacuo. In all cases,
CuCN was used as the catalyst at the first step, since it allowed retention of the highest
isolated yields for the products 20 upon a scale-up. It should be noted that product 20f
appeared to be unstable, and gradually decomposed after storing at 0 °C for more than
one week.
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Page 20 of 81
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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
O
1) NH OH·HCl
2
R1
RF
CuCN
KHF2
RF
O N
R1 2) NaHCO3
THF
MeOHH O
2
13
19
(9 : 1)
HO
RF
HO
HO
CHF2
CHF2
O
O
O
N
N
N
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
2
2
2
0a, RF =CHF2
0b, RF =CF3
0c, RF =CF CH3 63%
20f, RF =CF Br
92%
93%
20g, 92%
20h, 92%
2
2
72%
Scheme 4. Synthesis of alcohols 20.
Synthesis of 3-fluoroalkyl-substituted pyrazoles. In addition to the synthesis of
isoxazoles, the potential of 1-fluoroalkyl substituted ynones 13 was further
demonstrated by the preparation of pyrazoles containing functionalized side chain. In
particular, cyclization of ynones 13 with either N H or MeNHNH led to the compounds
2
4
2
2
2 and 23, respectively, in 72–95% yield (Table 5). Further deprotection of these
derivatives with KHF gave alcohols 24 and 25 in up to 97% yield. It was also found that
2
reaction of MeNHNH with ynones 13 at 0 °C gave compounds 23g
2
Table 5. Synthesis of pyrazoles 22–28.
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8
9
RF
O
RF
OH
RF
RF
KHF2
N H
2
4
N
R1
HN
N
R2
THF
R1
N
H
N
R1
N
MeOHH2O
H
(9 : 1)
13
28
22
24
RF
RF
RF
RF
MeNHNH2
1) KHF2
R1 MeOHH2O
9 : 1)
2) separation
(for 23a and 26a)
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
13
+
N
R2
or
N
R2
N
R1
N
N
N
THF
N
N
(
2
3a,b  major product
23g,h  the only product
26a,b
25
27
Exception:
O
CF CH
2
3
CH CF
F CH C
2 3
3
2
N H
2
CDI
4
HO
NH
N
N
THF
7%
CH Cl
2
2
OTBS
N
H
9
95%
OTBS
OTBS
13c
28c
22c
entry
RF
R1
22, 23 or 26
yield, %)
R2
24, 25 or 27
(
(yield, %)
1
2
CHF2
CHF2
CHF2
CF3
CH OTBS
22a (95)a
23a (–)
CH OH
24a (97)
2
2
25a (89)a,b,c
CH OTBS
CH OH
2
2
3
CH OTBS
26a (–)
CH OH
27a (6) a,b,c
25b (94)
N/A
2
2
4
CH OTBS
23b (86)a,d
26b (10) a,d
22c (92)b
23c (92)
23d (79)
23e (72)
22g (–)
CH OH
2
2
5
CF3
CH OTBS
CH OH
2
2
6
CF CH
CH OTBS
CH OH
24c (95)
N/A
2
3
3
2
2
7
CF CH
CH OTBS
CH OH
2
2
2
8
C2F5
CH OTBS
CH OH
N/A
2
2
9
CF Br
CH OTBS
CH OH
N/A
2
2
2
10
CHF2
CHF2
(CH ) OTBS
(CH ) OH
24g (82)b
25g (77)b
2 2
2 2
11
(CH ) OTBS
23g (–)
(CH ) OH
2 2
2 2
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1
2
CHF2
CHF2
CH(CH )OTBS
22h (93)
23h (88)
CH(CH )OH
24h (95)
25h (97)
3
3
13
CH(CH )OTBS
CH(CH )OH
3
3
a
The reaction was carried out on 85–120 g scale.
The yield for two steps is given.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
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5
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8
9
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1
2
3
4
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
b
c
Isolated after separation of 25a and 27a by vacuum distillation
Isolated after separation of 23b and 26b by column chromatography
d
and 23h from 13g and 13h, respectively, as single products, whereas substrates 13a,b
led to the target pyrazoles 23a,b and 26a,b as ca. 9:1 regioisomeric mixtures. In the
case of the compounds 25a and 27a (89% and 6% yield, respectively), the individual
isomers were separated by distillation of the products obtained after deprotection of the
crude mixture of 23a and 26a. Conversely, for 23b and 26b, the separation was
achieved by column chromatography immediately after the cyclization step, and led to
individual products 23b and 26b in 86% and 10% yields, respectively.
For all ynones 13 (except 13c), direct preparation of aromatic products 22 was
achieved without isolation of intermediate 5-hydroxypyrazolines 28. Although derivatives
28 were usually present in the reaction mixture along with main products 22 prior to
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work-up, the concentration of the reaction mixture in vacuo and filtration through silica
plug led to the rapid dehydration of 28 to give 22. Yet, the reaction of 13c with N H
2
4
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
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5
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8
9
0
1
2
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4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
resulted in 5-hydroxypyrazoline 28c as a single product (97% yield). Thus, intermediate
2
8c was further dehydrated using CDI in CH Cl to give 22c in 95% yield.
2
2
Synthesis of drug analogues. One of the primary goals of this work was to develop an
efficient synthetic route towards fluoroalkyl-substituted isoxazoles and pyrazoles, which
can be easily used for isosteric replacement of heterocyclic moieties in biologically
active compounds. In previous reviews, promising building blocks for drug discovery
were referred to as the compounds containing a structural moiety which can be
considered as attractive for medicinal chemistry, and one or several functional groups
with predictable and controllable chemical reactivity.53,54 From this point of view, a
number of functionalized derivatives bearing carboxylic acid, amine, aldehyde, ketone,
halide, azide functional groups were synthesized from alcohols 20, 21, 24 and 25 (see
Supporting Information for more details). Application of the obtained building blocks was
demonstrated by the preparation of antidepressant Isocarboxazid39 and anxyolitic
40
Mepiprazole analogues (Scheme 5). In order to access the CHF -substituted Isocar-
2
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H N
2
O
O
CrO3
EtOH
O
NH
HO
HO
aq. H SO
H SO
N H ·H O
O
2
4
2
4
2
4
2
N
F
N
F
N
F
acetone
0%
reflux
92%
EtOH
N
F
O
O
O
9
O
O
F
F
F
H
F
N
2
1a
29a
30
31
Bn
N
H
N
Boc O
DMAP
CH Cl2
O
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
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7
8
9
0
O
H
Boc
O
Isocarboxazid
2
) PhCHO, NaBH(OAc)3
F
N
2
F
Bn
N
H
N
Bn
N
N
F
42% yield
for 3 steps
H
THF
O
N
F
O
3
2
33
Isocarboxazid analogue
HN
N
F
F
F
F
Cl
F
F
F
F
36
N
N
O
HN
CrO3
aq. H SO
AlH3
THF
O
O
N
N
CDI, THF
92%
2
4
N
N
O
acetone
3%
71%
N
N
N
N
O
O
4
N
OH
OH
20g
35g
Cl
Cl
Cl
34
Mepiprazole analogue
3
7
Mepiprazole
Scheme 5. Synthesis of Isocarboxazid analogue 33 and Mepiprazole analogue 34.
boxazid analogue, carboxylic acid 29a was obtained from 21a and converted to its ethyl
ester 30 (92% yield). The treatment of 30 with aq N H led to the formation of unstable
2
4
hydrazide 31, which was immediately converted to 32 by reductive amination of
benzaldehyde. However, purification of the intermediate 32 appeared to be problematic;
therefore, crude 32 was subjected to the reaction with Boc O to give Boc-protected
2
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Isocarboxazid analogue 33, which was obtained as a pure product after column
chromatography (42% yield for three steps).
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
Preparation of Mepiprazole analogue 34 was achieved from 20g by a three-step
reaction sequence. After Jones oxidation of alcohol 20g, carboxylic acid 35g was
subjected to amide coupling with amine 36 (92% yield). Further reduction of amide
moiety in 37 with LiAlH gave the target 3-(difluoromethyl)isoxazole-containing analogue
4
of Mepiprazole 34 (71% yield).
CONCLUSIONS
Reaction of fluoroalkyl-substituted ynones with NH OH, N H and MeNHNH was
2
2
4
2
used for efficient preparation of 3- or 5-fluoroalkyl isoxazoles and pyrazoles on up to
200 g scale. The studied methods allowed to obtain the target products as single
regioisomers by either 1,2- or 1,4-addition route. Thorough and careful optimization of
the reaction conditions was performed for each of the key steps of the synthetic
sequences. This allowed preparation of 5-fluoroalkyl isoxazoles with up to 79% overall
yield for cyclization and dehydration steps, 3-fluoroalkyl isoxazoles – with up to 93%
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6
overall yield for cyclization and side chain desilylation steps, and 3-fluoroalkyl pyrazoles
–
with up to 95% at the cyclization step. Importantly, using a series of previously
0
1
2
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4
5
6
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8
9
0
1
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9
0
1
2
3
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5
6
7
8
9
0
unknown fluorinated ynones allowed to increase the scope of fluoroalkyl substituents for
incorporation to heterocyclic motifs, as well as provided possibility for extensive
functionalization of the side chain. The utility of obtained building blocks for isosteric
replacement of alkyl substituted isoxazole and pyrazole moieties was shown by the
synthesis of fluorinated Isocarboxazid and Mepiprazole analogues. Therefore, the
discussed protocols and fluorinated derivatives might provide new opportunities for lead
optimization programs.
EXPERIMENTAL SECTION
General Methods. The solvents were purified according to the standard procedures.55
All starting materials were purchased from commercial sources. Melting points were
measured on automated melting point system. Column chromatography was performed
using Kieselgel Merck 60 (230–400 mesh) as the stationary phase. H, 19F and 13
1
C
NMR spectra were recorded at 500 MHz or 400 MHz, 470 or 376 MHz, and 126 MHz or
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1
01 MHz, respectively. 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, Taras Shevchenko National University of Kyiv.Mass
spectra were recorded on an Agilent 1100 LCMSD SL instrument (chemical ionization
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
(APCI), electrospray ionization (ESI)) and Agilent 5890 Series II 5972 GCMS instrument
(electron impact ionization (EI)). The X-ray diffraction data sets were collected with a CCD
diffractometer for compound 29a, 35g, 24h. CCDC- 1945644 (29a), - 1945645 (35g), -
1945642 (24h) contain 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.
General procedure for the preparation of the compounds 13. To a pre-cooled (–78 ºC)
solution of alkyne 15 (1.00 mol) in THF (1 L) under argon, 2.5 M solution of n-BuLi (1.00
mol, 400 mL) in hexanes was added dropwise. The resulting mixture was warmed to –
15 ºC, stirred for additional 15 min at the same temperature and then cooled to –40 ºC.
The corresponding ethyl ester 14 (1.00 mol) was added dropwise, followed by BF ·Et O
3
2
(1.05 mol, 129.6 mL) in one portion. The resulting mixture was allowed to warm to rt and
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4
4
4
4
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5
5
5
5
5
5
6
stirred overnight. After the reaction was complete, the mixture was quenched by
addition of cold saturated solution of NH Cl (500 mL) at 0 ºC under argon flow. The
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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0
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0
organic layer was separated and concentrated under reduced pressure, whereas the
aqueous layer was extracted with EtOAc (4×350 mL). The residue obtained after
evaporation of THF and EtOAc solution was combined, washed with brine (2×150 mL),
dried over anhydrous Na SO and concentrated under reduced pressure. Purification of
2
4
the final product was achieved by distillation in vacuo.
5-((tert-Butyldimethylsilyl)oxy)-1,1-difluoropent-3-yn-2-one (13a). Yield 309 g (80%),
from 265 g of tert-butyldimethyl(prop-2-yn-1-yloxy)silane (15a) and 193 g of
1
CHF CO Et. Colorless liquid, bp = 80–81 C/7.7 mbar. H NMR (400 MHz, CDCl ): δ
2
2
3
13
1
5
.77 (t, J = 54.0 Hz, 1H), 4.55 (s, 2H), 0.92 (s, 9H), 0.16 – 0.12 (m, 6H) ppm. C{ H}
NMR (126 MHz, CDCl ): δ 175.1 (t, J = 30.0 Hz), 108.8 (t, J = 253.0 Hz), 99.1, 79.9,
3
19
5
1.7, 25.8, 18.3, –5.2 ppm. F NMR (376 MHz, CDCl ): δ –126.5 (d, J = 54.0 Hz) ppm.
3
+
+
GC−MS (m/z): 248 (M ), 197 (M – CHF ). Anal. Calcd. for C H F O Si: C, 53.20; H,
2
11 18
2
2
7.31. Found: C, 52.81; H, 7.12.
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5
-((tert-Butyldimethylsilyl)oxy)-1,1,1-trifluoropent-3-yn-2-one (13b).56 Yield 180 g
(
81%), from 142 g of of tert-butyldimethyl(prop-2-yn-1-yloxy)silane (15a) and 119 g of
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
1
CF CO Et. Colorless liquid, bp = 61–62 C/7.7 mbar. H NMR (400 MHz, CDCl ): δ 4.57
3
2
3
13
1
(
s, 2H), 0.92 (s, 9H), 0.14 (s, 6H) ppm. C{ H} NMR (126 MHz, CDCl ): δ 167.0 (q, J =
3
19
1
4
2.4 Hz), 114.8 (q, J = 288.1 Hz), 100.5, 78.9, 51.7, 25.7, 18.3, –5.3 ppm. F{ H} NMR
+
+
(
376 MHz, CDCl ): δ –78.8 ppm. GC−MS (m/z): 209 (M – C(CH ) ), 197 (M – CF ).
3
3 3
3
Anal. Calcd. for C H F O Si: C, 49.61; H, 6.43. Found: C, 49.41; H, 6.47.
11
17
3
2
6-((tert-Butyldimethylsilyl)oxy)-2,2-difluorohex-4-yn-3-one (13c). Yield 61.4 g (83%),
from 48.0 g of tert-butyldimethyl(prop-2-yn-1-yloxy)silane (15a) and 40.0 g of
1
CF (CH )CO Et. Colorless liquid, bp = 53–54 C/1 mbar. H NMR (400 MHz, CDCl ): δ
2
3
2
3
13
1
4
.54 (s, 2H), 1.76 (t, J = 18.6 Hz, 3H), 0.92 (s, 9H), 0.14 (s, 6H) ppm. C{ H} NMR (101
MHz, CDCl ): δ 176.7 (t, J = 36.0 Hz), 116.5 (t, J = 249.0 Hz), 98.0, 80.0, 51.7, 25.7,
3
1
1
9.7 (t, J = 25.2 Hz), 18.3, –5.2 ppm. 19F{ H} NMR (376 MHz, CDCl ): δ –100.1 ppm.
3
+
+
GC−MS (m/z): 205 (M – C(CH ) ), 197 (M – CF CH ). Anal. Calcd. for C H F O Si:
3
3
2
3
12 20
2
2
C, 54.93; H, 7.68. Found: C, 55.02; H, 7.49.
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