Cu-Catalyzed Synthesis of Fluoroalkylated Isoxazoles from Commercially Available Amines and Alkynes

Article abstract of DOI:10.1021/acs.orglett.7b04028

A one-pot protocol for the construction of fluoroalkylated isoxazoles directly from commercially available amines and alkynes is described. The reaction is scalable, operationally simple, regioselective, mild, and tolerant of a broad range of functional groups. As such, it could be viewed as a click synthesis of fluoroalkylated isoxazoles. Preliminary mechanistic investigations reveal that the transformation involves an unprecedented Cu-catalyzed cascade sequence involving R_fCHN₂.

Full text of DOI:10.1021/acs.orglett.7b04028

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cu-Catalyzed Synthesis of Fluoroalkylated Isoxazoles from
Commercially Available Amines and Alkynes
Xiao-Wei Zhang, Wen-Li Hu, Suo Chen, and Xiang-Guo Hu*
National Engineering Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang, 330022, China
S
* Supporting Information
ABSTRACT: A one-pot protocol for the construction of
fluoroalkylated isoxazoles directly from commercially available
amines and alkynes is described. The reaction is scalable,
operationally simple, regioselective, mild, and tolerant of a
broad range of functional groups. As such, it could be viewed
as a “click synthesis” of fluoroalkylated isoxazoles. Preliminary mechanistic investigations reveal that the transformation involves
an unprecedented Cu-catalyzed cascade sequence involving RfCHN2.
itrogen heterocycles are core structures of numerous
expanded the utility of fluorinated diazoalkanes for the synthesis
Nbioactive natural and unnatural compounds. A recent of various fluorinated compounds. Unsurprisingly, fluorinated
diazoalkanes have found applications in the synthesis of FSAs.
For example, in 2013, Ma and co-workers developed a silver-
mediated [3 + 2] cycloaddition of CF3CHN2 for the synthesis
CF3-substituted pyrazoles (Figure 1b).7a In 2015, Mykhailiuk
solved the long-standing synthetic problem of difluoromethyl
diazomethane (HCF2CHN2) and applied it for the construction
of CF2-substituted pyrazoles (Figure 1b).9d In 2017, Jamison and
co-workers developed an unified synthesis of CF3- and CF2-
substituted pyrazoles under continuous flow conditions.
However, in all these elegant examples, fluorinated diazoalkanes
are used as three-atom components and therefore are only
suitable for the synthesis of FSAs with two or more nitro-
gens.7,9a−e,10b,11f We report herein the successful utilization of
RfCHN2 for the synthesis of fluoroalkylated isoxazole (FIO), one
important FSA containing one nitrogen in the ring.12
analysis showed that nearly 60% of small-molecule drugs
approved by the US FDA contain at least one N-heterocycle.1
On the other hand, fluoroalkyl groups, CF3 and CF2 in particular,
often impart desirable physical and biological properties when
incorporated into organic molecules.2 The combination of these
two features has thus generated a great number of
pharmaceuticals, agrochemicals, and related candidates,3 with
fluoroalkyl-substituted azoles (FSAs) being particularly notable
(Figure 1a).
Fluorinated diazoalkanes (RfCHN2)4 have emerged as useful
building blocks largely owing to the pioneering work from
Carreira and co-workers, who in 2010 reported a convenient
protocol for in situ generation and application of CF3CHN2.5
Since then, contributions from the groups of Carreira,6 Ma,7
Molander,8 Mykhailiuk,9 Koenigs,10 and others11 have greatly
Generally, FIOs are prepared by condensation of 1,3-
dicarbonyl compounds or their equivalents; intramolecular
cyclization of alkynyl oximes; or 1,3-cycloaddion of nitrile
oxide with alkynes.13 Unfortunately, however, all of the reported
methods suffer from at least one of the following problems:
narrow substrate scope; forcing reaction conditions; requirement
for the handling of unstable intermediates; low efficiency; and
lack of regioselectivity. More importantly, poor step- or pot-
economy14 is a common roadblock for easy access to FIOs
because the requisite starting materials such as nitrile oxides
usually need to be synthesized in a multistep fashion.15
In order to address the aforementioned limitations, we aimed
to develop a mild, efficient, and pot-economical reaction for the
synthesis of FIOs. Based on our understanding of the chemistry
11e
of RfCHN2 and inspired by the recent successful transition-
metal-catalyzed couplings of alkynes with diazo-compounds,16
we envisioned that a one-pot approach could be developed via
the cascade sequence shown in Figure 1c. Although the research
Figure 1. FSA-containing bioactive compounds and syntheses of FSAs
from alkynes and RfCHN2.
Received: December 27, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b04028
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
groups of Fu,17a Fox,17b and Wang17c−e reported the coupling of
alkynes with nonfluorinated diazo-compounds, and Ma18
documented the reaction of alkynes with CF3CHN2, there
remain significant challenges associated with our hypothetical
cascade reaction. For example, the trapping of alkyne-derived
carbenoid 2 with nitrosonium ion (NO+) is unprecedented even
for nonfluorinated diazo-compounds.19 Further, the reaction
could entail competing pathways such as β-F elimination20 and
protodemetalation.17d Finally, identifying appropriate conditions
to integrate all of the individual steps into a one-pot reaction
could be viewed as a daunting task.
Our first objective was to realize the reaction in a stepwise
fashion. We initiated our studies by preparing a solution of
HCF2CHN2 in either CHCl3 or CH3CN according to the
method of Mykhailiuk.9d Based on the known reactivity of
alkynes with diazo-compounds,17,18 we evaluated a variety of CuI
and PdII species as the catalyst. Different Lewis acid additives
along with tert-butyl nitrite (TBN) for the generation nitro-
sonium ion were also screened (Table S1).21 After extensive
experimentation, we discovered that the desired FIO 5a could be
obtained in 28% yield with ZnCl2 as the acid additive and CuI as
the catalyst (Scheme 1), thus verifying the feasibility of our
reaction design.
(entries 4−7). Other metal additives gave no product under
otherwise identical conditions (entries 1−3). The reaction with
ZnBr2 showed a strong dependence on the solvent, with CHCl3
affording the best result (entries 8−10). Increasing the amounts
of HCF2CH2NH2 (6a) and TBN to 3 molar equiv each gave the
desired product in an optimized yield of 87% (entry 11). Control
experiments showed that both CuI and ZnBr2 were indispensable
(entries 12−15). It is noteworthy that neither of the possible side
products 77a,9d,11f or 818 was observed under the optimized
conditions.
With the optimized conditions in hand (entry 11, Table 1), we
proceeded to test the scope of the reaction with respect to both
the alkyne and amine components (Scheme 2). Initially, the
alkyne component was varied while keeping the amine
component constant (6a). The reaction tolerates a variety of
Scheme 2. Substrate Scope
Scheme 1. Optimized Condition for the Synthesis of Isoxazole
with Prior Formation of HCF2CHN2
Encouraged by this preliminary result, we next investigated
whether the reaction could still occur if the HCF2CHN2 was
generated in situ rather than being formed in a discrete operation
(Table 1 and Tables S2−S3). To our delight, we found the
reaction proceeded successfully if certain zinc salts were included
within the mixture, with ZnBr2 providing the best outcome
Table 1. Optimized Conditions for Synthesis of Isoxazole 5a
without Prior Formation of HCF2CHN2
a
entry
additives (equiv)
solvents
yield (%)
1
2
3
4
5
6
7
8
9
10
LiCl (2.0)
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
THF
0
0
AlCl3 (2.0)
AgNO3 (2.0)
ZnI2 (2.0)
0
0
Zn(OTf)2 (2.0)
ZnCl2 (2.0)
ZnBr2 (2.0)
ZnBr2 (2.0)
ZnBr2 (2.0)
ZnBr2 (2.0)
ZnBr2 (2.0)
no CuI
0
43
66
52
3
toluene
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
48
87
0
b
11
b
12
b
13
b
no ZnBr2
0
14
ZnBr2 (1 equiv)
CuI (5 mol %)
42
73
b
15
a
b
a
Isolated yield. 3 equiv of HCF2CHNH2 and TBN were used.
Yield on gram-scale; R1 = 4-MeO-Bz; R2 = 4-NO2-Bz.
B
DOI: 10.1021/acs.orglett.7b04028
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
substitution patterns and functional groups on the phenyl-
acetylene moiety. Para- (5a−5p), ortho- (5q−5s), and meta-
substituted examples (5t−5bb) all smoothly afforded the desired
isoxazoles in good to excellent yields. A wide variety of functional
groups are tolerated including methoxy (5e, 5q), halide (5f−5h),
trifluoromethyl (5i), cyano (5j), nitro (5k, 5t), ester (5i, 5s),
acetyl (5s), sulfinyl (5n), sulfonyl (5o), sufoxyl (5p), alkenyl
(5s), protected amino (5x−5bb), and free hydroxyl (5v) groups.
The fact that some common protecting groups (5w−5aa) are
compatible with the reaction conditions suggests that the
method is potentially useful for other functionalized substrates.
The reaction exhibits good chemoselectivity, as no ring nitration
occurs even for the electron-rich compounds (e.g., 5e, 5q, 5v,
5w).22 Generally, the yields of substrates with electron-
withdrawing substituents were slightly lower than those with
electron-donating substituents. Besides the phenylacetylenes
described thus far, bicylcoaryl (5ee) and heteroaryl (5ff−5ii)
substituted acetylenes are also viable substrates. Also, the
reaction is not limited to (hetero)aryl substituted acetylenes:
styryl and aliphatic alkynes also gave rise to the corresponding
products (5jj−5ll), albeit in somewhat lower yields. With respect
to the fluorinated amine component, the method is equally
efficient with trifluoroethylamine (6b); all of the corresponding
CF3-substituted isoxazoles (9a−9qq) were obtained in com-
parable yields to their CF2 counterparts. Finally, other two
fluoroalkylamines (6c−6d) are also suitable for this reaction,
giving 10a and 11a in 83% and 86% yields, respectively. It should
be pointed out that only one regioisomer was observed for all of
the 78 examples tested, and 66 products obtained are
unprecedented in the literature. Furthermore, the reaction is
also scalable: for example, 9g was obtained in 82% yield on gram-
scale with a lower catalyst loading (5 mol % CuI). The structures
of 5k, 5y, and 9c were confirmed by means of X-ray
crystallographic analysis (CCDC 1577898, 1577906,
1577913). Because of the efficiency, generality, regioselectivity,
chemoselectivity, and mildness of the reaction conditions, as well
as the ready availability of all of the reagents, this method could
be viewed as a “click synthesis”23 of fluoroalkylated isoxazoles.
To gain an insight into the mechanism of this transformation, a
series of control experiments were conducted (Scheme 3). First,
acetylide (17) failed to afford 5a under the standard conditions
(Scheme 3d), suggesting that 17 is not an intermediate. In
contrast, an independently prepared zinc acetylide (18) did
afford the product 5a under the same conditions (Scheme 3e),
indicating that 18 could be a true intermediate. (Organozinc
reagents are known to be formed by reaction of alkynes with zinc
salt in the presence of an organic base.)27 This is also supported
by the observation of gradual dissolution of ZnBr2 during the
course of the reaction. Successful reaction of 18 with a stock
solution of CF3CHN225 (Scheme 3f) further indicated that the
zinc acetylide may be the intermediate, as well as the involvement
of fluorinated diazoalkane. Finally, although the presumed oxime
intermediate 4a could not be isolated, an independently prepared
sample of 4a did cyclize readily under the standard conditions
(Scheme 3g).
A possible mechanism is proposed based on the control
experiments conducted in this work (Scheme 4). The reaction is
Scheme 4. Mechanistic Proposal
initiated by the formation of Cu-carbene A from diazo-
compound B, generated in situ via the reaction of amine C
with tert-butyl nitrite. Transmetalation of Cu-carbene A with zinc
acetylide D, followed by a migratory insertion of the resulted E,
yields copper carbenoid F. A nitrosonium ion, generated from
tert-butyl nitrite, then captures carbenoid F to afford oxime H
after tautomerization. Finally, 5-endo-dig cyclization of oxime H
affords the isoxazole product I.
In summary, we have developed a one-pot protocol for the
construction of fluoroalkylated isoxazoles directly from
commercially available amines and alkynes. The reaction is
scalable, operationally simple, regioselective, mild, and tolerant
of a broad range of functional groups (78 examples tested, 66
products obtained are unprecedented). As such, it could be
viewed as a “click synthesis” of fluoroalkylated isoxazoles.
Preliminary mechanistic investigations reveal that this trans-
formation involves an unprecedented cascade sequence,
featuring trapping of a carbenoid, generated from reaction of
an alkyne and RfCHN2, with a nitrosonium ion. An additional
salient feature of this reaction is that no prior formation and
transfer of potentially dangerous RfCHN2 is required. Develop-
ing a new cascade reaction employing RfCHN2 for the synthesis
of other types of fluoroalkylated heterocycles is actively being
pursued in this laboratory and will be reported in due course.
a
Scheme 3. Control Experiments
a
R = 4-Ph-Phenyl.
24
simple mixing of CF3CHN2 and CuI in CHCl3 (Scheme 3a)
suggested that Cu-carbene formation is facile in this trans-
formation.25 Second, an isotopically labeled substrate suffered
significant loss of deuterium (Scheme 3b), indicating that a
metalated alkyne is involved and that a possible reaction pathway
involving nitrile oxide is less likely;26 the fact that compounds
12−16 failed to react also suggests that the latter pathway is not
involved (Scheme 3c). Third, an independently prepared copper
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b04028.
Experimental details, analytical data (PDF)
C
DOI: 10.1021/acs.orglett.7b04028
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Accession Codes
Letter
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CCDC 1577898, 1577906, and 1577913 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: huxiangg@iccas.ac.cn.
ORCID
Xiao-Wei Zhang: 0000-0002-2262-4143
Xiang-Guo Hu: 0000-0002-5909-2582
Notes
(12) Nine drugs approved by FDA contain the isoxazole core; see ref
12.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank National Natural Science Foundation of China
(21502076), Natural Science Foundation of Jiangxi province
(20161BAB213068), and Outstanding Young Talents Scheme of
Jiangxi Province (20171BCB23039) for funding, and Dr. Luke
Hunter at UNSW for proof reading.
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DOI: 10.1021/acs.orglett.7b04028
Org. Lett. XXXX, XXX, XXX−XXX