Synthesis of trifluoromethylated isoxazoles and their elaboration through inter- and intra-molecular C-H arylation

Article abstract of DOI:10.1039/c6ob00970k

We report conditions for the preparation of a range of trifluoromethylated isoxazole building blocks through the cycloaddition reaction of trifluoromethyl nitrile oxide. It was found that controlling the rate (and therefore concentration) of the formation of the trifluoromethyl nitrile oxide was Critical for the preferential formation of the desired isoxazole products versus the furoxan dimer. Different conditions were optimised for both aryl- and alkyl-substituted alkynes. In addition, the reactivity at the isoxazole 4-position has been briefly explored for these building blocks. Conditions for intermolecular C-H arylation, lithiation and electrophile quench, and alkoxylation were all identified with brief substrate scoping that signifies useful tolerance to a range of functionalities. Finally, complementary processes for structural diversification through either intramolecular cyclisation or intermolecular cross-coupling were developed.

Full text of DOI:10.1039/c6ob00970k

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OrgaPnleicas&e BdoionmootlaedcjuulsatrmCahregminsistry
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DOI: 10.1039/C6OB00970K
Journal Name
ARTICLE
Synthesis of Trifluoromethylated Isoxazoles and Their Elaboration
Through Inter- and Intra-molecular C-H Arylation
Received 00th January 20xx,
Accepted 00th January 20xx
Jian-Siang Poha, Cristina García-Ruiza, Andrea Zúñigaa, Francesca Meronia, David C. Blakemoreb,
Duncan L. Brownea,c* and Steven V. Leya
DOI: 10.1039/x0xx00000x
We report conditions for the preparation of a range of trifluoromethylated isoxazole building blocks through the
cycloaddition reaction of trifluoromethyl nitrile oxide. It was found that controlling the rate (and therefore concentration)
of the formation of the trifluoromethyl nitrile oxide was critical for the preferential formation of the desired isoxazole
products versus the furoxan dimer. Different conditions were optimised for both aryl- and alkyl- substituted alkynes. In
addition, the reactivity at the isoxazole 4-position has been briefly explored for these building blocks. Conditions for
intermolecular C-H arylation, lithiation and electrophile quench, and alkoxylation were all identified with brief substrate
scoping that signifies useful tolerance to a range of functionalities. Finally, complementary processes for structural
diversification through either intramolecular cyclisation or intermolecular cross-coupling were developed.
www.rsc.org/
Introduction
Alternatively, a strategy involving the preparation of novel
fluorinated building blocks which are then incorporated in a
The addition of fluorine to organic molecules does a great deal
to alter chemical properties and behavior.1 For example, in
biologically active materials fluorine substituents can affect the
charge distribution, electrostatic surface and solubility of
chemical entities, often leading to positive outcomes.2 Perhaps
the most attractive property however is the ability to reduce
the rate of metabolism compared to non-fluorous congeners,
which ultimately leads to reduced dosing rates for both
patients and crops.3 Furthermore, in the area of materials
chemistry fluorous substituents can impart advantages such as
reduced band gaps and higher quantum efficiencies in OLED
devices.4
There are typically two strategic methods for introducing
fluorous substituents. The late stage introduction, which has
received much attention recently,5 is an important method,
particularly for taking advantage of the radioactive properties
of 18F labelled materials.6 Furthermore, with regards to
trifluoromethylation, this doctrine serves as a convenient
method to easily functionalise existing compound libraries,
convergent manner (a fluorous synthon approach) is also of
importance, particularly when it comes to scaling up the
preparation of the compound of interest.8 Common to both
strategic approaches is the fact that fluorine is not present in
many naturally occurring organic compounds and so any
reagents or building blocks must be derived from fluorine gas,
or other mineral derived fluorines (such as HF, SF4, SF6 or HOF)
thus requiring both highly skilled workers and specialised
equipment and safety protocols.
Recently, we and others have been exploring cycloaddition
methods to rapidly access
a
series of fluorinated
intermediates, from simple fluorous synthon starting
materials, that can further undergo a range of diverse
modifications.9 Here we report a robust protocol for the
preparation and cycloaddition of trifluoroacetonitrile oxide
with alkynes, followed by diversification via palladium-
catalysed inter- and intra-molecular C-H activation reactions.
We have also assessed the further derivatisation of these
systems via anion and cycloaddition chemistry.
usually through
a C-H, C-O, C-B, C-Sn or C-X bond
transformation and more recently that of a C-N bond.7
OH
Br
OH
H
OH
OMe
i) NH2OH HCl
ii) NBS, DMF
82% (2 steps)
N
N
NaOH
H2O/MeOH
F3C
F3C
F3C
3
1
2
Scheme 1: Preparation of CF3 nitrile oxide precursor
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View Article OCnlNine
results from initial conditions and brief substrate scoping
n-Bu
F
DOI: 10.1039/C6OB00970K
Br
O
O
OH
Br
(2 equiv)
R
O
O
H
N
N
O
N
N
N
N
R
F
Et3N in PhMe (1.5 equiv)
syringe pump over 45 mins
F3C
3
F3C
F3C
F3C
F3C 91%
F3C 63%
32%§
38%§
§ furoxan dimer clearly present in 19F NMR of crude rxn mixture
rate implications arising from initial screening
O
N
Ar
karyl
H
Ar
aryl-isoxazole
furoxan dimer
F3C
F3C
O
O
N
N
OH
base
N
N
khomodimer
N O
F3C
kN-O-gen
F3C
Br
CF3
4; trifluoromethyl-
3
kalkyl
H
Alk
nitrile oxide
O
alkyl-isoxazole
Alk
F3C
Experimental Observations: karyl > khomodimer > kalkyl | [4] is a common denominator to the formation of all products
Hypothesis: use kN-O-gen to control [4] and therefore maximise selectivity?
Scheme 2: Initial cycloaddition experiments and considerations
appears to be slower than the rate of furoxan formation. This
suggested that control could be obtained by reducing the
concentration of nitrile oxide relative to alkyne. Such control
could potentially be achieved by invoking pseudo first-order
conditions in nitrile oxide. This would be achieved by using a
syringe pump to deliver either the base or the nitrile oxide
precursor slowly to a flask containing all of the alkyne. With
this in mind we therefore optimized procedures for aryl and
alkyl alkynes separately, with particular attention to methods
that limit formation of the furoxan. For the optimization
studies of aryl alkyne cycloadditions, we used phenylacetylene
as the substrate. Firstly, the number of equivalents of alkyne
was assessed.
Results and Discussion
Our approach to the preparation of 3-trifluoromethyl
isoxazoles hinged on a nitrile-oxide [3 + 2] cycloaddition
reaction with alkyne substrates. Few examples of this
approach are known. In order to synthesize the desired 5-
substituted 3-trifluoromethylated isoxazoles via [3 + 2]
cycloaddition reactions, a stable nitrile oxide precursor for
trifluoroacetonitrile oxide was required. We decided to use
hydroximoyl bromide 3, prepared using a two-step procedure
(Scheme
1)
from
the
commercially
available
trifluoromethylated hemiacetal 1.10 Owing to the volatility of
both intermediate aldoxime 2 and hydroximoyl bromide 3,
these materials were extracted into an ethereal solution and
then stored and used from this stock in subsequent steps. 11
With the desired trifluoromethyl nitrile oxide precursor in
hand, we then focused on the [3 + 2] cycloaddition reaction
with terminal alkynes. Early attempts with the cycloaddition
reaction under similar conditions reported by Tanaka et al.
with a small variety of alkynes revealed that the yield of
isoxazole was rather dependent on the electronic properties of
the alkyne (Table 1).12 In general, more electron-deficient
alkynes (in particular, alkyl alkynes) appeared to undergo
slower cycloaddition with trifluoroacetonitrile oxide. Analysis
of the 19F NMR spectra of the crude reaction mixture for some
alkyl alkynes (Scheme 2) indicated the presence of furoxan
resulting from the unwanted dimerization reaction of
trifluoroacetonitrile oxide.13
optimisation for aryl alkynes
OH
(X equiv)
Ph
H
O
N
N
Ph
Et3N in PhMe (2 equiv)
syringe pump over Y min
F3C
Br
F3C
3
5a
Entry alkyne equivs (X) addition rate (Y) base/solvent
yielda
Et3N/PhMe
Et3N/PhMe
Et3N/PhMe
iPr2NEt/PhMe
Pyridine/PhMe
2,6-lutidine/PhMe
TBAF/THF
Na2CO3/H2O
Et3N/PhMe
1
2
3
4
5
6
7
8
9
1.0
2.0
3.8
2.0
2.0
2.0
2.0
2.0
2.0
2.0
45
45
45
45
45
45
45
45
5
70%
90%
93%
69%
9%
5%
2%
82%
81%
96%
10
120
Et3N/PhMe
We considered the rates of the reactions explored in the
context of these experimental observations. Empirically, the
preliminary evidence suggests that the rate of nitrile oxide
cycloaddition with aryl alkynes is greater or comparable to that
of the dimerization of the CF3 nitrile oxide, whereas the rate of
cycloaddition between the nitrile oxide and alkyl alkynes
(a) Yield of isolated product
Table 1: Optimisation for aryl alkyne cycloaddition
2 | J. Name., 2012, 00, 1-3
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Evidently, using a slower rate of base addition to controllably
unveil small amounts of nitrile oxide could further suppress
View Article Online
DOI: 10.1039/C6OB00970K
optimisation for alkyl alkynes
CN
OH
H
CN (2 equiv)
the unwanted dimerisation reaction, since the relative
concentration of the nitrile oxide compared to the alkyne was
low. We then focused our attention on alkyl alkynes using 5-
hexynenitrile as the substrate. Since it appeared that
suppression of furoxan formation was required to obtain good
yields of isoxazole, it was postulated that increasing the time
taken for base addition would be a simple modification to the
optimized procedure for aryl alkynes. Indeed, when the time
taken for base addition was progressively increased to 16 h
(Table 2, entries 1-3), higher yields of isoxazole 6a were
obtained; further increasing the time taken to 24 h (Table 2,
entry 4) had little effect on yield.14 With optimized conditions
for the cycloaddition reaction with aryl and alkyl alkynes
established, we decided to explore the scope of the reaction.
N
O
N
Et3N in PhMe (2 equiv)
syringe pump over Y min/h
F3C
Br
3
6a
yielda
F3C
base/solvent
Entry
addition rate (Y)
Et3N/PhMe
Et3N/PhMe
Na2CO3/H2O
Na2CO3/H2O
1
2
3
4
38%
58%
73%
74%
45 min
6 h
16 h
24 h
(a) Yield of isolated product
Table 2: Optimisation for alkyl alkyne cycloadditions
With 1.1 equiv of alkyne and dropwise addition via syringe
pump of 2 equiv Et3N/PhMe over 45 mins at r.t. (Table 1, entry
1), the corresponding isoxazole 5a was isolated in 70% yield.
Analysis of the crude reaction mixture by 19F NMR
spectroscopy indicated the presence of furoxan. Increasing the
alkyne equivalents to 2.0 and 3.8 gave yields of 90% and 93%
respectively (Table 1, entries 2 and 3), indicating that an excess
of alkyne relative to the nitrile oxide would be advantageous
to suppressing furoxan formation. We decided to use 2.0 equiv
of alkyne for subsequent reactions as it appeared that greater
excesses of alkyne provided diminishing returns in terms of
yield of desired isoxazole product. When a variety of bases
substrate scope for alkyl alkynes
OH
H
Alk (2 equiv)
O
N
N
Alk
Na2CO3 in H2O (2 equiv)
syringe pump over 16 h
F3C
Br
F3C
3
6
CN
OH
O
N
O
N
O
N
i
6b; 54%
6c; 74%
F3C
F3C
F3C
6a; 73%
were assessed only Et3N, Pr2NEt and Na2CO3 provided good
yields of isoxazole 5a (Table 1, entries 3, 4 and 8), whereas
weaker bases such as pyridine, 2,6-lutidine and TBAF produced
negligible yields of 5a (Table 1, entries 5-7). Finally, the rate of
base addition was assessed; when the time taken for addition
of Et3N was decreased to 5 min, isoxazole 5a was isolated in
81% yield (Table 1, entry 9). However, when the time taken
was increased to 2 h, isoxazole 5a was isolated in an improved
yield of 96% (Table 1, entry 10).
Br
Br
O
O
O
N
N
N
F3C
6f; 64%
[2.80 g]
6e; 75%
[2.75 g]
6d; 77%
[2.66 g]
F3C
F3C
HO
O
O
O
N
substrate scope for aryl alkynes
N
OH
(2 equiv)
Ar
H
O
N
N
Ar
F3C
6g; 62%
6h; 74%
F3C
Et3N in PhMe (2 equiv)
syringe pump over 2 h
F3C
Br
F3C
3
5
I
HN
N
N
N
F
Br
N
O
O
O
O
O
Br
N
O
O
O
F
N
N
N
O
F
N
N
N
5a; 96%
[5.13 g]
F3C
5c; 84%
5f; 60%
5b; 73%
6j; 56%
6k; 63%
6i; 65%
F3C
F3C
OMe
F3C
F3C
F3C
CN
n-Bu
Scheme 4: Scope of the alkyl alkyne cycloaddition
O
O
O
N
N
N
F3C
F3C
F3C
5d; 99%
5e; 84%
Scheme 3: Scope of the aryl alkyne cycloaddition
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For the aryl alkyne examples explored, both elecVtireownA-rtriciclehOanlninde
electron-poor systems underwent cycloaddition, with the
Pd-catalysed C-H cross-coupling of 3,5-disubstituted isoxazoles
DOI: 10.1039/C6OB00970K
O
O
(2 equiv)
Ar Br
latter proceeding in lower yield, perhaps due to a mismatch in
the electronics of the dipolarophile and 1,3-dipole. With
regard to the alkyl alkynes a variety of functional groups were
tolerated such as alkyl bromides, free alcohols, cyclopropanes,
nitriles and ketones (Scheme 3). In addition, we explored some
more exotic alkyl alkynes derived from nucleophilic aromatic
substitution of heteroaromatic halides with propargyl alcohol.
Of the three explored, all proceeded to the desired product in
yields greater than 50% (Scheme 4, 6i, 6j and 6k). For all of the
explored substrates the cycloaddition reaction showed
exclusive regioselectivity for the formation of 5-substituted
isoxazoles, an observation congruent with the literature.15
Several examples were also conducted on larger scale and
afforded greater than 2.5 grams of product in comparable or
greater yields to the smaller scale reactions (5a, 6d, 6e and 6f).
Having demonstrated a broad substrate scope we next wished
to explore the possibility of further manipulation of these 5-
substituted 3-trifluoromethylisoxazoles by the introduction of
functionality at the 4-position. Palladium-catalyzed C-H
activation of isoxazoles has been demonstrated by Fall et al. on
3,5-dimethylisoxazole and 3-methyl-5-phenylisoxazole, but
they note that electron-deficient isoxazoles were coupled
much less efficiently.16 Indeed, the intermolecular cross-
N
N
R
R
AcOK (2 equiv), PdCl2 (5 mol%)
DMA, 130 °C, 72 h
F3C
F3C
H
Ar
O
N
O
N
O
N
N
F3C
F3C
F3C
CF3
7a; 85%
7b; 87%
7c; 78%
O
O
N
O
N
N
N
F3C
F3C
F3C
O
OMe
7d; 60%
7e; 52%
7f; 47%
Scheme 5: Intermolecular C-H arylation
coupling
of
4-bromotoluene
and
5-phenyl-3-
Lithiation and electrophile quench of 3,5-disubstituted isoxazoles
trifluoromethylisoxazole (5a) resulted in only 38% conversion
to the desired 4-arylated isoxazole (7a), despite use of 5 mol%
PdCl2 and heating for 72 h. However, switching to 2 equiv aryl
bromide allowed the desired product 7a to be isolated in 85%
yield. Alternative aryl bromide coupling partners for 5-phenyl-
3-trifluoromethylisoxazole (5a), such as electron-rich, electron-
deficient and heterocyclic bromides, were assessed (Scheme 5)
and gave moderate to excellent yields. Further, 5-cyclopropyl-
3-trifluoromethylisoxazole (5g) could also be coupled to 3-
bromopyridine in 47% yield. Rather than undergoing cross-
coupling of the C-H bond at the 4-position, lithiation at this
position was also demonstrated using nBuLi.
O
i) n-BuLi, THF, -78 °C, 30 min
O
N
N
R
R
ii) electrophile, 10 min
F3C
F3C
iii) NH4Cl
H
E
O
O
N
O
N
N
H
H
O
B
F3C
F3C
F3C
O
O
O
E+ = DMF;
8a; 94%
E+ = i-PrOBPin;
8b; 96%
E+ = DMF;
8c; 34%
Scheme 6: Lithiation and electrophilic quench
elaboration of homobenzylic bromide 6e through alkene formation
OH
N
N
O
kalkene > karyl
>
Br
R
i) Ambersep -OH resin
ii) filter
khomodimer > kalkyl
furoxan formation less
of a problem here
O
O
R
Cl
O
N
N
N
Et3N in PhMe (2 equiv)
dropwise over 5 min
F3C
F3C
F3C
9
10
6e
examples of isoxazole-isoxazoline scaffolds available by this approach
N
N
N
O
N
O
O
O
CF3
O
O
O
O
OMe
CF3
N
N
N
N
10a; 99%
10b; 92%
10c; 82%
10d; 47%
F3C
F3C
F3C
F3C
Scheme 7: elimination and nitrile oxide cyclisation
4 | J. Name., 2012, 00, 1-3
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agent for an aromatic ring bearing a nucleophilic heteroatom
and an adjacent halide function.
View Article Online
DOI: 10.1039/C6OB00970K
strategy to elaborate 3-trifluoromethyl-isoxazole building blocks
Nu
O
LG
alkylate
N
O
X
Nu
preparation of 5,6,6 precursors
N
X
OH
O
F3C
H
Br
K2CO3, DMF
60 °C, 3 h
N
O
F3C
X
O
N
X
F3C
6d
11
[Pd], Ar-B(OH)2
F3C
intramolecular
C-H cross-
coupling
[Pd]
intermolecular
C-X cross-coupling
CF3
NC
O
O
O
O
O
O
O
Nu
N
N
N
N
I
I
Br
O
Nu
N
Ar
F3C
F3C 11a; 77%
F3C
11b; 67%
F3C
11c; 72%
O
F3C
5,X,6 tricyclic systems
Ph
Scheme 8: Proposed strategy for rapid structural diversification through
complementary cross-coupling
O
N
O
N
O
O
I
I
F3C
11d; 41%
F3C
11e; 67%
Again for the 5-phenyl-3-trifluoromethylisoxazole (5a)
substrate, lithiation was straightforward (Scheme 6).
Quenching of the thus formed organometallic species with
DMF led to the corresponding aldehyde whereas a boron
electrophile (i-PrOBPin) could be used to afford the boronic
ester product 8b in good yields. Notably, whilst the 5-
cyclopropyl-3-trifluoromethylisoxazole (5g) also participated in
this chemistry; the aldehyde product 8c was isolated in
reduced yield compared to the phenyl analogue.
N
N
O
O
N
O
O
N
I
I
F3C
11f; 82%
F3C
11g; 50%
preparation of 5,7,6 precursors
HO
O
N
O
O
Br
NaH, THF
60 °C, 3 h
N
Other strategies to rapidly elaborate this ring system hinged
around the versatile fluorinated, bromoalkyl building blocks 6d
and 6e. Indeed, we found that homobenzylic bromide (6e) was
an excellent surrogate for the 5-alkenyl-3-trifluoromethyl-
isoxazole (9) through an elimination process. This alkene was
most optimally accessed by stirring 6e in the presence of the
polymer-supported base, Ambersep® OH resin, followed by
filtration of the resin and storage of the resultant volatile
alkene (9) in an ethereal solution. The reactivity of this
versatile alkene building block (9) was then explored in the
context of nitrile oxide cycloaddition chemistry (Scheme 7). In
this instance it is well documented that the rate of alkene
cycloaddition is greater than that of the nitrile oxide homo-
dimerisation process. Indeed, the nitrile oxide derived from
cinnamaldehyde underwent smooth cycloaddition to give the
isoxazole-isoxazoline bicyclic moiety (10a). Electron-rich and
electron-poor benzaldehyde derivatives also proceeded
without incident affording the 4-methoxy and 4-
trifluoromethyl variants 10b and 10c in excellent yield. The
cycloaddition reaction of electron-poor alkene building block 9
with the electron-poor trifluoromethyl nitrile oxide (4) did also
afford the desired isoxazole-isoxazoline bicyclic product, but in
reduced yield (47%) relative to the other examples explored,
again likely due to a mis-match in electronics.
X
F3C
F3C
6d
12
X
O
O
O
O
N
N
F
F3C
F3C
Br
Br
12a; 92%
12b; 62%
O
O
Cl
O
O
N
N
F3C
F3C
N
I
I
12c; 20%
12d; 70%
O
O
O
O
N
N
O
F3C
F3C
Br
Br
12e; 50%
12f; 86%
Scheme 9: Conditions and scope for alkylation reaction
The halide on these resulting products could then potentially
undergo two different cross-coupling reactions leading to
rapid structural diversification.17
A strategy for derivatisation of the trifluoromethylated
bromoalkyl building block 6d, is described in scheme 8. The
approach commences by using this material as an alkylating
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O
O
DOI: 10.1039/C6OB00970K
N
N
O
O
Pd catalysis
H
I
MeO
MeO
13
14
Entry
Base
Solvent
Ligand
Additive
Time (h)
Conversion
Isol. Yield
1
2
3
4
5
6
7
8
9
DMA
DMF
Dioxane
DMA
DMF
Dioxane
DMA
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
72
48
48
72
72
72
72
72
72
98
98
12
31
-
-
21
-
-
40
-
KOAc
a
-
-
a
PdCl2 (5 mol%)
Base (2.0 equiv)
solvent, 130 °C
K2CO3
-
-
-
a
a
Cs2CO3
DMF
Dioxane
-
-
a
10
11
12
13
14
DMF
DMF
DMA
DMA
DMA
TBAB
TBAB
TBAB
TBAB
-
24
24
24
24
24
98
98
98
98
98
PCy3
dppf
57
0
42
36
52
Pd(OAc)2 (5 mol%)
Base (4.0 equiv)
Ligand, Additive (2.0 equiv)
solvent, 100 °C
K2CO3
PtBu3.HBF4
PCy3.HBF4
Xantphos
15
16
17
18
19
DMA
DMA
DMA
DMA
DMA
P(Ph)3
P(Ph)3
P(Ph)3
P(4-F-Ph)3
P(4-Cl-Ph)3
TMBA
PhCO2H
PivOH
PivOH
PivOH
16
16
16
16
16
98
98
98
98
98
47
38
51
60
44
Pd(OAc)2 (5 mol%)
Base (4.0 equiv)
Ligand, Additive (0.3 equiv)
solvent, 65 °C
K2CO3
a) starting material recovered
O
O
N
N
Pd catalysis
O
O
F3C
F3C
H
I
11a
15a
Entry
1
Base
Solvent
DMA
Ligand
P(Ph)3
Additive
PivOH
Time (h)
16
Conversion
98
Isol. Yield
85
Pd(OAc)2 (5 mol%)
Base (4.0 equiv)
Ligand, Additive (0.3 equiv)
solvent, 65 °C
K2CO3
P(4-F-Ph)3
2
DMA
PivOH
16
98
90
3
DMA
-
16
98
73
P(4-F-Ph)3
Table 3 & 4: Optimisation of the intramolecular C-H arylation reaction
One cross-coupling would be intermolecular and could likely develop the cross-coupling conditions. Initially this was
be controlled by appropriate choice of base and inclusion of a investigated on para-methoxyphenyl substrate 13. Repeating
coupling partner (boronic acid), whereas the other coupling our previously successful conditions for the intermolecular
would be an intramolecular C-H functionalizing ring formation case on this substrate afforded 12% isolated yield of the
leading to a novel series of trifluoromethylated tricyclic intramolecular product (14) but 98% conversion of the starting
scaffolds. Indeed this approach also offers significant scope for material. The main byproduct was that derived from
varying linker size in the initial alkylation step and therefore deiodination (Table 3, entry 1). Exploring DMF and 1,4-dioxane
the subsequent central ring size of the tricyclic system. as solvent options, it was found that in DMF the reaction
Commencing with the alkylation of a variety of ortho- afforded an improved 31% yield of the cyclised product (Table
iodophenols with bromide 6d, we found that optimal 3, entry 2). Replacement of the KOAc base with K2CO3 and
conditions consisted of gentle heating to 60 °C in DMF using Cs2CO3 did not lead to dramatic changes in yield. Taking
potassium carbonate as base (scheme 9). Conditions for the inspiration from the literature on intramolecular C-H arylation
alkylation of ortho-iodobenzyl alcohols were better conducted reactions of benzene systems via proton abstraction, we made
with sodium hydride in THF, which furnished several a more significant change in our approach.18
homologated products (scheme 9). Next we turned to the
intramolecular C-H arylation reaction and looked to further
6 | J. Name., 2012, 00, 1-3
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catalytic intramolecular C-H coupling
catalytic intermolecular coupling
R
O
O
Pd(OAc)2 (5 mol%)
P(4-F-C4H4)3 (5 mol%)
PdCl2(PPh3)2 (5 mol%)
Ar-B(OH)2
N
N
R
O
O
O
N
O
F3C
F3C
K3PO4 (3 equiv)
DME:H2O (1:1), 65 °C, 2 h
H
PivOH (30 mol%), K2CO3 (3 equiv)
DMA, 65 °C, 3-6 h
R
F3C
X
H
O
O
N
O
N
O
N
N
O
O
O
O
F3C
F3C
F3C
F3C
N
15a; 90%
15b; 87%
O
15c; 57%
15d; 58%
Ph
O
N
O
O
N
O
N
N
O
O
O
N
O
F3C
F3C
F3C
F3C
CN
15e; 39%
15f; 51%
15h; 60%
15g; 65%
F3C
OMe
MeO
MeO
N
CF3
O
O
O
O
O
O
N
O
N
O
O
N
N
16a; 60%
16b; 71%
16c; 99%
16d; 95%
H
F3C
F3C
F3C
F3C
H
H
H
Scheme 10: Conditions and scope for alkylation reaction
Table 3, entries 10-14 describe the results from the changed (15h) was also prepared in 60% yield using these C-H arylation
catalyst system, now including a ligand, additive and two conditions.
further equivalents of base, whilst dropping the temperature In order to demonstrate the diversity of this scaffold through
by 30 °C and reaction time down to 1 day. Notably, in almost cross-coupling we also found optimal conditions for the
all
cases
the
outcome
was
improved,
with intermolecular Suzuki-Miyaura reaction. Inclusion of the
tricyclohexylphosphine ligand and tetrabutylammonium requisite boronic acid and switching both the base and solvent
bromide as additive providing the superior result at 57% system permitted smooth access to the linear products 16a-d
isolated yield. Indeed, we surveyed several other literature in good to excellent yield. Notably in the latter cross-coupling
reports19 and found that the conditions reported by Fagnou et cases, no intramolecular cyclised product was detected
al. offered further improvements.19a Under these conditions, signalling that the reactivity and structural diversity can truly
which included reduced loading of additive and use of be switched by a simple change in reaction conditions.
triarylphosphines, we made gains on both reaction time and
temperature where the optimal conditions consisted of
heating to 65 °C over 16 hours (Table 3, entry 18). Notably,
Conclusions
P(4-F-Ph)3 as ligand outperformed PPh3, providing a 10%
improvement in isolated yield (Table 3, cf entries 17 and 18).
Applying these optimal conditions, as developed for the less
reactive model substrate, to the 3-trifluoroisoxazole 11a we
were pleased to find that the tricyclic product (15a) could be
isolated in 90% yield (Table 4, entry 2). Control reactions
showed that P(4-F-Ph)3 still provides notable benefit as does
the presence of pivalic acid. With these optimal conditions, we
then applied them to a range of the alkylated materials to
successfully furnish a range of 5,6,6 tricyclic compounds
including the pyridine derivatives 15c and 15f in moderate to
excellent yields (Scheme 10). One example of a 5,7,6 tricycle
In summary, we report conditions for the preparation of a
range of trifluoromethylated isoxazole building blocks though
trifluoromethyl nitrile oxide cycloaddition. It was found that
controlling the rate (and therefore concentration) of the
formation of the trifluoromethyl nitrile oxide was critical for
the preferential formation of the desired isoxazole products
versus the furoxan dimer. Different conditions were optimised
for both aryl- and alkyl- substituted alkynes. In addition, the
reactivity at the isoxazole 4-position was then briefly explored
for these building blocks. Conditions for intermolecular C-H
arylation, lithiation and electrophile quench, and alkoxylation
were all identified with brief substrate scoping that signifies
useful tolerance to a range of functionalities. Finally we
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Journal Name
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developed complementary processes for structural
diversification through either intramolecular cyclisation or
intermolecular cross-coupling, with a series of 5,6,6 and 5,6,7
tricyclic systems being formed.
8
9
Acknowledgements
We thank the Cambridge Home and European Scholarship
Scheme (JSP) and the EPSRC (SVL grant numbers
EP/K009494/1 and EP/M004120/1) for financial support.
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some disposable syringes would degrade and become very
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8 | J. Name., 2012, 00, 1-3
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L. Elliott and M. C. Willis, Angew. Chem. Int. Ed., 2010, 49,
7958.
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trifluoromethyl isoxazoles
fluorinated building-block
55 examples
R
R
O
O
OH
Br
H
R
N
N
N
R1
F3C
F3C
F3C
[broad substrate scope]
[rapid scaffold diversification]
preparation
elaboration