A new reagent for direct difluoromethylation

Article abstract of DOI:10.1021/ja211422g

Molecular scaffolds containing alkylfluorine substituents are desired in many areas of chemical research from materials to pharmaceuticals. Herein, we report the invention of a new reagent (Zn(SO₂CF₂H) ₂, DFMS) for the inn

Full text of DOI:10.1021/ja211422g

Communication
pubs.acs.org/JACS
A New Reagent for Direct Difluoromethylation
Yuta Fujiwara,§,‡ Janice A. Dixon,§,‡ Rodrigo A. Rodriguez,§ Ryan D. Baxter,§ Darryl D. Dixon,§
Michael R. Collins,† Donna G. Blackmond,§ and Phil S. Baran*,§
§Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
†Department of Chemistry, La Jolla Laboratories, Pfizer Inc., 10770 Science Center Drive, San Diego, California 92121, United States
S
* Supporting Information
ABSTRACT: Molecular scaffolds containing alkylfluorine
substituents are desired in many areas of chemical research
from materials to pharmaceuticals. Herein, we report the
invention of a new reagent (Zn(SO2CF2H)2, DFMS) for
the innate difluoromethylation of organic substrates via a
radical process. This mild, operationally simple, chemo-
selective, and scalable difluoromethylation method is
compatible with a range of nitrogen-containing hetero-
arene substrates of varying complexity as well as select
classes of conjugated π-systems and thiols. Regiochemical
comparisons suggest that the CF2H radical generated from
the new reagent possesses nucleophilic character.
he difluoromethyl group (CF2H) is an intriguing
structural motif that has great potential in the areas
T
of pharmaceuticals, agrochemicals, and materials.1−5 In the
area of medicinal chemistry, the CF2H unit is of special
interest for its use in isostere-based drug design.6 As a
lipophilic hydrogen bond donor, CF2H substitution offers an
alternative to more traditional hydrogen bond donors while
improving membrane permeability. For example, the
difluoromethyl group has been utilized as a thiol mimic in
the context of HCV NS3 protease inhibitors, successfully
mimicking the cysteine CH2SH P1 element in the parent
compounds.7 It has also been used as a hydroxamic acid
hydroxyl isostere in a series of COX-2 and 5-LOX dual
inhibitors, likely diminishing the metabolic toxicity expressed
by some hydroxamic acids.8 While several methods exist for
the fluorination and alkylfluorination of organic substrates,
strategies for direct difluoromethylation are less common,
particularly in the context of heteroarene substrates. In this
Communication, the invention of a reagent to accomplish
the mild, direct, scalable, and predictably selective difluoro-
methylation of heteroarenes and related structures is reported.
Currently, all known methods for heteroarene difluoro-
methylation rely on prefunctionalization through a programmed
approach (Figure 1A). Perhaps the most widely known strategy
involves difluorination of aldehydes using (diethylamino)sulfur
trifluoride (DAST).9,10 Heteroarene−CF2H compounds may
also be accessed through a copper-catalyzed cross-coupling/
decarboxylation sequence,11 or via radical debromination from
a heteroarene−CF2Br precursor.12 Although these methods
boast impressive levels of reactivity and site selectivity, the need
for methods achieving the direct transfer of the CF2H unit has
been explicitly voiced in a recent review.13
Figure 1. Invention of a new difluoromethylation reagent.
The pioneering work reported by Minisci on the decarbox-
ylative generation of alkyl radicals and subsequent addition to
heteroarenes (a form of innate14 C−H functionalization) inspired
initial forays into this area.15 Thus, difluoroacetic acid was the first
CF2H source that was tested on caffeine (1) under a variety of
oxidative conditions (Figure 1B). However, this strategy was
unsuccessful, necessitating the exploration of alternative methods
for generating CF2H radicals. The only previous example of direct
radical transfer of a CF2H unit was reported by Chen and co-
workers in the context of additions to olefins and alkynes (no
other substrate classes reported) using non-commercial and
operationally problematic HCF2I gas as a precursor.16
Received: December 6, 2011
Published: January 9, 2012
© 2012 American Chemical Society
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Table 1. Scope of C−H Difluoromethylation of Heteroarene Substrates
a
Heterocycle (1.0 equiv), DFMS (2.0 equiv), tert-butyl hydroperoxide (3.0 equiv), TFA (1.0 equiv), 23 °C; isolated yields of chromatographically
b
pure products are displayed, unless otherwise noted. Both indole and 1-(2,4-dimethylfuran-3-yl)ethanone were unreactive, giving recovered starting
material. C2:C4:C6, 1.5:1.5:2. C2:C4:C6, 1:1:2. C2:C4:C6, 3:1:2. Reaction showed incomplete conversion after 12 h, and a second addition
of DFMS (2.0 equiv) and tert-butyl hydroperoxide (3.0 equiv) was done. C4:C5, 4:1. Heterocycle (1.0 equiv), DFMS (3.0 equiv), tert-butyl
hydroperoxide (4.0 equiv), 23 °C.
c
d
e
f
g
h
In contrast, we have previously demonstrated the ease and
practicality associated with the use of stable fluoroalkyl metal
sulfinate complexes for the generation of trifluoromethyl radicals
and subsequent addition to heteroarenes.17 The seemingly simple
extension of this approach to difluoromethylation was without
precedent and required extensive experimentation.18 Ultimately,
after several strategies were evaluated, difluoromethanesulfonyl
chloride was recognized as a convenient, commercially available
starting point for the synthesis of a variety of different
difluoromethylsulfinate reagents (Figure 1C). Using caffeine (1)
as a model substrate, systematic variation of the metal counterion
led to the identification of Zn(SO2CF2H)2 (3, DFMS) as the
optimum precursor for the CF2H radical. DFMS is an easily
prepared, air-stable, free-flowing white powder whose structure
was confirmed by X-ray crystallographic analysis and shown to
exist as a polymer in the solid state (see Supporting Information
for more details).
In most cases, substrates with multiple potential reaction sites
exhibit high levels of regioselectivity, commonly producing only
one observable regioisomer with C−H functionalization occurring
at electron-deficient positions.17 It should be noted that all of the
compounds illustrated in Table 1 are chemical entities with
heretofore unreported synthetic procedures. In addition to the
heteroarene substrates listed in Table 1, other organic substrates
are also reactive toward difluoromethylation by the described
process (Table 2). Aromatic thiols exhibit unexpected reactivity
a
Table 2. Difluoromethylation of Thiols and Enones
With this new reagent in-hand, the scope of heteroarene
difluoromethylation was evaluated on a broad cross-section of
heterocyclic space. Many substrates showed good reactivity toward
DFMS under the standard reaction conditions using tBuOOH in a
CH2Cl2/H2O solvent system, although select substrates suffered
from poor conversion. In these cases, a second addition of DFMS
and tBuOOH was added after 12−24 h to drive the reaction
toward completion. It was also found that TFA showed improved
rate and conversion for selected nitrogen heteroarene substrates,
but was not essential to achieve the desired reactivity for most
cases. Pyridines (5−10, 12, 22), pyrroles (14, 15), pyrimidines
(18), quinoxalines (16), pyrazines (17), xanthines (2, 19, 20),
purines (21), quinoline (23), thiadiazoles (13), and pyridinones
(11) are all competent participants in the described method,
which is tolerant of several potentially sensitive functional groups.
a
Standard conditions were followed, and yields were obtained after silica
b
gel chromatography. DFMS (1.0 equiv) and tert-butyl hydroperoxide
(1.5 equiv) were used. Second addition of DFMS (2.0 equiv) and tert-
butyl hydroperoxide (3.0 equiv). α,α,α-Trifluorotoluene was used
instead of dichloromethane. Keto:enol, 1:5.
c
d
e
toward the CF2H radical, leading to the generation of
difluoromethyl thioethers. Radical difluoromethylation was also
successful in the context of other electron-deficient π-systems such
as α,β-unsaturated enones.
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Figure 2. Regiochemical comparison of innate difluoro- and trifluoromethylations. Isolated yields after preparative HPLC purification.
In addition to the predictable site-selectivity observed in the
difluoromethylation of simple small-molecule substrates, innate
C−H difluoromethylation of complex reacting partners with many
potential reactive sites is also predictable. As shown in Figure 2, the
site-selectivity of difluoromethylation depends on the combined
electronic properties of the reacting π-system and incoming radical
species. This point is illustrated through a comparison between CF3
and CF2H radical additions to dihydroquinine and varenicline
(marketed in the U.S. as the prescription medication Chantix by
Pfizer). In both cases, high levels of selectivity are observed for CF3
and CF2H radical addition, in spite of the multiple potentially
reactive sites. For both dihydroquinine and varenicline, innate
radical C−H trifluoromethylation takes place at the most electron-
rich position within the arene rings (C7 and C5, giving 32 and 33,
respectively).17 Conversely, difluoromethylation occurs exclusively
at electron-poor sites adjacent to heteroatoms within the hetero-
arene rings (both at C2, giving 30 and 31). The orthogonality of
these two approaches is a powerful example of the ability to
fine-tune an approach to alkylfluorination when consider-
ing the innate reactivity and electronic nature of the two
reacting components.
leads to significant reversal of regiochemistry, favoring the C3-
CF2H isomer (6-C3) in 1.5:1.0 ratio. Although C3 selectivity is
modest under these conditions, the change in selectivity is significant
considering that the C3-CF2H product is inaccessible under
standard reaction conditions.
In summary, a new reagent (DFMS, 3) for direct difluoro-
methylation has been invented to access compounds of high
value that, in almost all cases, were hitherto unknown. DFMS is
effective for the direct transfer of a CF2H unit to various organic
substrates including heteroarenes, α,β-unsaturated enones, and
aromatic thiols via user-friendly, scalable, open-flask condi-
tions.19,20 Changes in regioselectivity may be promoted by varying
the organic cosolvent in the context of 4-substituted pyridines.
Further examination of this and other mechanistic features
is ongoing and will be reported in due course. DFMS
has recently been commercialized by Sigma-Aldrich (product
no. L510084).
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and analytical data for all new
1
compounds, including H, 13C, and 19F NMR and CIF files.
Although many substrates listed in Table 1 produce a single
observable regioisomer, it is possible to access alternative substitu-
tion in some cases by judicious choice of organic solvent media.
As shown in Figure 3, 4-acetylpyridine shows exceptional regio-
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
pbaran@scripps.edu
■
Author Contributions
‡These authors contributed equally.
ACKNOWLEDGMENTS
■
We are grateful to Prof. Arnold Rheingold and Dr. Curtis E.
Moore for X-ray crystallographic analysis. Financial support for
this work was provided by the NIH/NIGMS (GM-073949),
the Uehara Memorial Foundation (postdoctoral fellowship for
Y.F.), the NSF (predoctoral fellowship for R.A.R.), and Pfizer
Inc. (postdoctoral fellowship for R.D.B.).
Figure 3. Solvent effects on regioselectivity. aStandard conditions were
followed. bA second addition of DFMS (2.0 equiv) and tert-butyl
hydroperoxide (3.0 equiv) was done.
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