Difluoromethylation of Terminal Alkynes by Fluoroform

Article abstract of DOI:10.1021/acs.orglett.5b01778

The difluoromethylation of terminal alkynes through the use of fluoroform as a source of difluorocarbene is described. The choice of solvents and bases was found to be crucial for the transformation. A series of terminal alkynes 1 were nicely converted into the corresponding difluoromethyl alkynes 2 using potassium tert-butoxide in n-decane in moderate to good yields. Functional groups such as methoxy, dimethylamino, and bromo as well as phenyl, heteroaryl, and sterically demanding naphthyl were well tolerated under the reaction conditions. One-step transformations of difluoromethyl alkynes 2 to difluoromethylated isoxazoles 3 and 1,2,3-triazoles 4 were also achieved.

Full text of DOI:10.1021/acs.orglett.5b01778

Letter
pubs.acs.org/OrgLett
Difluoromethylation of Terminal Alkynes by Fluoroform
Satoshi Okusu,† Etsuko Tokunaga,‡ and Norio Shibata*,†,‡
‡
†Department of Frontier Materials and Department of Nanopharmaceutical Sciences, Nagoya Institute of Technology, Gokiso,
Showa-ku, Nagoya 466-8555, Japan
S
* Supporting Information
ABSTRACT: The difluoromethylation of terminal alkynes through the use of fluoroform as a source of difluorocarbene is
described. The choice of solvents and bases was found to be crucial for the transformation. A series of terminal alkynes 1 were
nicely converted into the corresponding difluoromethyl alkynes 2 using potassium tert-butoxide in n-decane in moderate to good
yields. Functional groups such as methoxy, dimethylamino, and bromo as well as phenyl, heteroaryl, and sterically demanding
naphthyl were well tolerated under the reaction conditions. One-step transformations of difluoromethyl alkynes 2 to
difluoromethylated isoxazoles 3 and 1,2,3-triazoles 4 were also achieved.
he synthesis of organofluorine compounds has attracted a
great deal of attention in the past few decades in the
difluorocarbene mechanism is involved in the transformatio-
n.11a,c,d Although these methods are useful for the synthesis of
difluoromethyl alkynes, HCF2Cl is a hazardous, ozone-depleting
substance. Alternative shelf-stable reagents can also be prepared
from HCF2Cl.11c,d Burton and Hartgraves reported an organo-
metallic approach for the direct difluoromethylation of alkynes
using a (difluoromethyl)cadmium reagent. This method also
required environmentally toxic HCF2I.11b Hence, a more
efficient and sustainable method for the difluoromethylation of
alkynes is required. As part of our research program on the
development of difluoromethylation reactions,12 we eventually
turned to the recently focused fluorinated raw material,
fluoroform (HCF3, HFC-23).
T
pharmaceutical and agrochemical industries.1 In particular, late-
stage direct fluoro-functionalization reactions are advantageous
in the synthesis of medicinally attractive fluorinated molecules
rather than the use of a fluorinated building block strategy, since
they rapidly access a large variety of fluorine-containing drug
candidates with structural diversity for prompt use in biological
screenings.2−4 Hence, the development of efficient methods for
fluoro-functionalization reactions such as trifluoromethylation3
and fluorination4 is becoming a main trend in this field. Among
fluoro-functionalization reactions, the difluoromethylation re-
action is the next target to be developed from the viewpoint of
isosterism in medicinal chemistry.5 The difluoromethyl (CF2H)
moiety behaves as an isosteric and isopolar group when linked to
hydroxy (OH)6 and thiol (SH)7 units. Moreover, the CF2H unit
has an acidic proton and thus acts as a more lipophilic hydrogen
donor than OH and NH groups through hydrogen bonding.8
Therefore, the replacement of OH, SH, and NH groups by CF2H
is a useful isosterism strategy for molecular modification of
original drugs and novel drug design. Although many methods
exist for the direct incorporation of a CF2H unit into target
positions,9 difluoromethylation of terminal alkynes is generally
more challenging than that of O-, S-, and N-nucleophiles since
C−H acidity is lower than heteroatom-H acidity.10 There are
only a few reported examples for the difluoromethylation of
terminal alkynes.11 In 1996, Kitazume and Konno succeeded in
the difluoromethylation of terminal alkynes using chlorodifluoro-
methane (HCF2Cl) and lithium acetylides.11a Hu and co-
workers showed the difluoromethylation of terminal alkynes with
a shelf-stable reagent, S-(difluoromethyl)-S-phenyl-N-tosylsul-
foximine.11c Furthermore, the same authors also reported that
tributyl(difluoromethyl)ammonium chloride is effective for the
difluoromethylation of terminal alkynes.11d In all these cases, a
Fluoroform is an ozone-friendly, nontoxic, and cheap
trifluoromethyl compound available in large quantities. Although
the use of HCF3 for organic synthesis had been problematic,
taming HCF3 for trifluoromethylation has been realized in the
past few years.13−16 One of the difficulties of treating HCF3 for
trifluoromethylation is the lability of the trifluoromethyl
carbanion (−CF3), which rapidly transforms to more stabilized
difluorocarbene.17 The electrostatic repulsions between carban-
−
ion and the p-orbital of the fluorine atom in CF3 induce the
formation of difluorocarbene with the release of a fluoride anion,
which is stabilized by the overlap between a vacant carbene
orbital and fluorine p-orbitals (Figure 1a).
Researchers have overcome the issue of lability of trifluor-
omethyl carbanion by using copper13 or potassium salts14 and a
sterically demanding superbase15 as well as a classical method
using DMF hemiacetal stabilization (Figure 1b).16 In this
context, we came up with the idea of using HCF3 as an
Received: June 19, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01778
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Difluoromethylation of 1a by HCF3
b
run
base
solvent
yield (%)
1
t-BuOK
t-BuONa
t-BuOLi
KOH
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
toluene
33
NR
NR
NR
0
2
3
4
5
KHMDS
NaH
Figure 1. (a) Rapid transformation of trifluoromethyl carbanion to
difluorocarbene due to electrostatic repulsions. (b) Fluoroform for
trifluoromethylation vs (c) difluoromethylation.
6
NR
NR
NR
18
7
P2-Et
8
PhOK
toluene
9
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
toluene
inexpensive, environmentally benign source of difluorocarbene,
and not trifluoromethyl carbanion, for organic synthesis (Figure
1c).
10
11
12
13
14
15
p-xylene
32
nPrCN
NR
NR
52
During an early stage of our investigation on this topic,18
Dolbier et al. reported very nice contributions for the
difluoromethylation of heterocentered nucleophiles using
HCF3 via in situ generation of difluorocarbene to furnish O-,
N- and S-CF2H products.18 However, there is no report on the
difluoromethylation of terminal alkenes by HCF3.19 We disclose
herein the first example of difluoromethylation of terminal
alkynes 1 by HCF3 to provide difluoroalkynes 2 in good yields.
The selection of both solvent and base is of prime importance to
obtain good yields for this transformation. Difluoromethylated
products 2 serve as precursors for medicinally attractive
difluoromethylated heterocycles such as isoxazoles and triazoles
via 1,3-cycloaddition and click reactions (Scheme 1).
1,4-dioxane
n-decane
n-decane
n-decane
d
d
c
85 (60)
,
e
72
a
The reaction of 1 with HCF3 (excess) was carried out in the presence
b
of base (5 equiv) in solvent (0.1 M) at 80 °C. Determined by 19F
NMR using a crude mixture with trifluorotoluene as the internal
standard. Isolated yield. 10 equiv of tBuOK was used. The reaction
was carried out at 100 °C.
c
d
e
explored with a variety of substrates selected in order to establish
the generality of the process (Scheme 2). Aromatic rings
substituted with either electron-donating or -withdrawing
substituents, such as methoxy 2a, dimethylamino 2b, phenyl
Scheme 1. Difluoromethylation of Terminal Alkynes 1 with
HCF3 and Their Transformation to Heterocycles
Scheme 2. Difluoromethylation of Terminal Alkynes 1 Using
HCF3
a,b
We initiated our investigation with the reaction of
ethynylanisole (1a) by HCF3 in solvent at 80 °C (Table 1).
The difluoromethylation of 1a by HCF3 in the presence of t-
BuOK (5.0 equiv) in mesitylene was attempted, and a desired
difluoromethyl alkyne 2a was obtained in 33% yield (run 1). The
base was next screened to improve yield (runs 2−8). However,
the reaction did not proceed when other bases, such as t-BuONa,
t-BuOLi, KOH, P2-Et, and PhOK, were used. Compound 1a was
decomposed to give a complex mixture under KHMDS
conditions (run 5). Upon screening solvents, we found that
the choice of solvent is very important in this transformation, and
n-decane produced a good result with 52% yield of 2a in the
presence of t-BuOK at 80 °C (run 13). Further improvement was
observed by using 10 equiv of t-BuOK (run 14). When the
reaction was carried out at 100 °C, the yield decreased slightly
(run 15).
a
The reaction of 1 with HCF3 (excess) was carried out in the presence
b
With suitable conditions in hand, the scope of the
difluoromethylation of terminal alkynes 1 using HCF3 was
of t-BuOK (10 equiv) in n-decane (0.1 M) at 80−120 °C. Isolated
yield.
B
DOI: 10.1021/acs.orglett.5b01778
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Organic Letters
Letter
2c, and bromo 2d, were tolerated. Meta- and ortho-substituted
aryl alkyne derivatives were also accepted (2e−g). A
benzothiophene-substituted alkyne 2h was compatible with the
same reaction conditions. The sterically demanding naphthyl-
substituted alkynes also afforded the corresponding products 2j
and 2k in moderate yields. Furthermore, the fluorene-substituted
alkyne also produced the desired product 2l in 38% yield.
Finally, a regioselective one-step conversion of 2 into the
medicinally attractive heterocycles was carried out to show the
utility of 2 (Scheme 3). First, the 1,3-dipolar cycloaddition of
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, analytical data (HRMS), CIF information,
1
and copies of H, 13C, and 19F NMR spectra. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.orglett.5b01778.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: nozshiba@nitech.ac.jp.
Notes
Scheme 3. Transformations of 2 to Medicinally Attractive
Isoxazoles 3 and Triazoles 4
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was financially supported in part by the Platform
for Drug Discovery, Informatics, and Structural Life Science from
MEXT Japan, the Advanced Catalytic Transformation (ACT-C)
from the Japan Science and Technology (JST) Agency, Scientific
Research (B) (25288045), Hoansha Foundation, and Kobayashi
International Scholarship Foundation.
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