Difluoroacetic Acid as a New Reagent for Direct C?H Difluoromethylation of Heteroaromatic Compounds

Article abstract of DOI:10.1002/chem.201704261

A technically simple procedure for direct C?H difluoromethylation of heteroaromatic compounds using off-the-shelf difluoroacetic acid as the difluoromethylating reagent has been developed. Mono-difluoromethylation versus bis-difluoromethylation is controlled as the result of the reaction temperature. The reactions described here enable access to the late-stage C?H mono- and bis-difluoromethylation for preparation of tool compounds for chemical biology and provide access to this hitherto untapped substituent for drug discovery.

Full text of DOI:10.1002/chem.201704261

A Journal of
Accepted Article
Title: Difluoroacetic Acid as a New Reagent for Direct C-H
Difluoromethylation of Heteroaromatic Compounds
Authors: Truong Thanh Tung, Søren Brøgger Christensen, and John
Nielsen
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COMMUNICATION
Difluoroacetic Acid as a New Reagent for Direct C-H
Difluoromethylation of Heteroaromatic Compounds
Truong Thanh Tung, Søren Brøgger Christensenand John Nielsen*
Abstract:
A
technically simple procedure for direct C-H
chemists, biologists, and pharmacologists to investigate the
properties of such bioisosters.
difluoromethylation of heteroaromatic compounds using off-the-shelf
difluoroacetic acid as the difluoromethylating reagent has been
developed. Mono-difluoromethylation versus bis-difluoromethylation
is controlled as the result of the reaction temperature. The reactions
described here enable access to the late-stage C–H mono- and bis-
difluoromethylation for preparation of tool compounds for chemical
biology and provide access to this hitherto untapped substituent for
drug discovery.
The most well-known strategy for the introduction of a
difluoromethyl group on aromatic rings is deoxyfluorination of
aldehydes using (diethylamino)sulfur trifluoride (DAST) and its
derivatives.[10] However, the low functional group compatibility of
these methods has limited its broad application in practice.
Currently, synthetic chemists pay great attention to the
development of novel metal-catalyzed difluoromethylation
reactions.[9] Nevertheless, these reactions rely on substitution of
a halogen atom,[11,12a-f] a boronic acid,[12g,h] a triflyloxy group[11b] or
diazonium salt[12i] with the difluoromethylated sources,
respectively. The preparation of difluoromethylated compounds
Approximately 20-25 % of marketed drugs contain fluorine
atoms revealing that this particular element plays a pivotal role in
modern drug discovery and development.[1,2] Introduction of
fluorine atoms in lead compounds enhance the druggability by
transforming the physicochemical properties as well as habitually
improving both chemical and metabolic stability.[1,3] Whereas
fluorine atoms and trifluoromethyl groups have been introduced
in a large number of drugs,[1,2] the difluoromethyl (CF2H) moiety is
much less in common. Three examples are roflumilast [for
treatment of asthma and chronic obstructive pulmonary disease
(COPD)],[2] pantoprazole [for treatment of gastroesophageal
reflux disease (GERD)] and eflornithine [for treatment of sleeping
disease (trypanosimiasis)].[3d,4] In the cases of roflumilast and
pantoprazole, the introduction of the difluoromethyl moiety
improved the pharmacokinetic properties enabling the use of the
drug in the clinic. In contrast, the ability of the two fluorine atoms
to function as leaving groups makes difluoroornithine
(eflornithine) an electrophilic suicide inhibitor of ornithine
decarboxylase.[3d]
via silver-catalyzed decarboxylation of α-fluoroarylacetic acids[12j]
,
α,α-difluoroarylacetic acids[12k] were also reported.[12l] To date,
only one method for innate C-H functionalization of N-containing
heteroaromatic with the difluoromethyl radicals has been reported
deploying zinc difluoromethanesulfinate (DFMS) in stoichiometric
amounts as the key difluoromethylating reagent (Scheme 1).[13,14]
However, this procedure is mainly focused on mono-
difluoromethylation. The use of DFMS does not enable the
selectivity, controllability of bis-difluoromethylation toward mono-
difluoromethylation and vice versa.
The presumption that the difluoromethyl group is
a
hydrophobic hydrogen donor being a bioisoster of hydroxy, amino
and sulfanyl groups has inspired studies of the effect of replacing
these groups with difluoromethyl moieties.[5,6] However, these
studies have been hampered by the limited number of synthetic
routes available for the introduction of the CF2H into
heteroaromatic compounds.[7-9] Thus,
convenient and direct synthetic method would enable medicinal
a technically simple,
Scheme 1. Previous approaches to direct difluoromethylation and current
discovery of direct mono- and one-step bis-difluoromethylation.
[*]
Truong Thanh Tung, Prof. Dr. Søren Brøgger Christensen, Prof. Dr.
John Nielsen.
Herein, we wish to report the direct and innate C-H
functionalization and mono-selective introduction of one
difluoromethyl moiety into heteroaromatic compounds using
difluoroacetic acid as the difluoromethyl radical source. The
methodology furthermore offers for the first time the opportunity
to introduce two difluoromethyl moieties in a controllable manner
by varying the reaction conditions.
Department of Drug Design and Pharmacology
University of Copenhagen
Universitetsparken 2, 2100 Copenhagen Ø, Denmark
E-mail: soren.christensen@sund.ku.dk (S. B. Christensen);
john.nielsen@sund.ku.dk (J. Nielsen).
As part of a recent project on the design and synthesis of
fusaric acid analogues,[15] we recently applied the Minisci reaction
to introduce alkyl groups to the pyridine ring via a well-established
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201704261
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COMMUNICATION
radical process.[16,17] To our delight, in the presence of
difluoroacetic acid, a difluoromethylated derivative was obtained
by a silver(I)/persulfate-catalyzed reaction (Table 1, entry 2). This
exciting discovery encouraged us to develop and optimize a new
protocol for difluoromethylation of heteroaromatic rings using off-
the-shelf difluoroacetic acid and to further investigate the scope
and limitations of this novel reaction.
salts such as iron(II) sulfate or copper(I) sulfate were tested and
found to be inferior (Table 1, entries 20-23). These observations
made us adopt the reaction conditions showed in entry 3, Table
1
as the preferred standard conditions for the mono-
difluoromethylation.
Mono-difluoromethylation of a number of N-heteroaromatic
substrates including some commonly appearing in
The conditions listed in Table 1 were screened. A ratio of
0.5 equivalent of silver(I) nitrate (AgNO3) and 5 equivalent of the
oxidant potassium persulfate (K2S2O8) afforded the best yields
(Table 1, entry 3). Decomposition was observed if higher ratios of
K2S2O8 and AgNO3 were used (Table 1, entry 4). Heating is
required as demonstrated by a yield of less than 5 % if the reaction
is run at room temperature (Table 1, entry 5).
pharmaceutically interesting heteroaromatic scaffolds like
pyridine, pyrimidine, pyrazine, quinoline, quinoxaline and selected
natural products was successfully performed (Scheme 2). The
standard reaction conditions in general afforded a product, in
which one difluoromethyl group was regioselectively attached to
the ring in the position neighboring the nitrogen atom (C-2). The
selectivity of the substitution was also observed when
heterocyclic scaffold contained multiple potentially reactive
positions. Moreover, the reaction is compatible with the presence
of halogen atoms in the molecule (compounds 5, 6, 11, 13,
Scheme 2). The practicality and scalability of the reaction was
demonstrated by the preparation of compound 1 from 1 g of
methyl isonicotinate using lower amount of AgNO3 (20 mol%) and
K2S2O8 (2.5 equiv., Scheme 2). In case of 8, 8´, 9, 11, 15, the low
yields obtained when using the standard reaction condition.
However, a significant improvement of the yield was observed by
adding H2SO4 to support the protonation process (See SI). Some
limitations of the present procedure are illustrated by the finding
that indole, caffeine and 1-methylisoquinoline did not react under
the standard conditions.
Table 1. Optimization of reaction conditions.
Yield
En
try
Solvent
(+H2O)a
[Ag+]b
Oxidation
(equiv.)c
Add.d
T °C
(%)e
1
2
ACN
ACN
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgDFAi
AgClO4
AgF
K2S2O8(1)
K2S2O8(3)
K2S2O8(5)
K2S2O8(7)f
K2S2O8(5)
K2S2O8(5)
K2S2O8(5)
K2S2O8(5)
K2S2O8(5)
K2S2O8(5)
K2S2O8(5)
tBuOOH(1-5)
tBuOOH(1-5)
(NH4)2S2O8(1-5)
H2O2(1-5)
K2S2O8(5)
K2S2O8(5)
K2S2O8(5)
K2S2O8(5)
K2S2O8(5)
K2S2O8(5)
K2S2O8(5)
K2S2O8(5)
-
50
50
13
50
71
55
<5
10
n.rh
n.r
n.r
n.r
n.r
n.r
<5
11
<5
7
-
3
ACN
ACN
-
50
4
-
50
5
ACN
-
rtg
6
Acetone
DCM
EtOH
MeOH
Dioxane
DMF
ACN
-
50
7
-
rt-40
rt-50
rt-50
rt-50
rt-50
rt
8
-
9
-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
-
-
-
ACN
-
50
ACN
-
50
ACN
-
50
ACN
-
50
ACN
-
50
12
32
27
30
n.r
21
n.r
ACN
-
50
ACN
AgOTf
AgNO3
-
-
50
ACN
FeSO4
FeSO4
Cu2SO4
Cu2SO4
50
ACN
50
ACN
AgNO3
-
50
ACN
50
a2:1 (v/v). b0.5 equivalent of AgNO3 gives the best conversion rate in our studies.
cequivalents are given in parentheses. d0.1 equivalent when using as addictive
to AgNO3 and 0.5 equivalent when using as catalyst. eYields are based on 19F-
NMR using 4-fluorobenzoic acid as internal standard. fDecomposition and yield
reduction was observed (by complicated TLC chromatograms with many
inseparable spots and complicated UPLC-MS) when increasing the amount of
K2S2O8 to over 5 equiv. gr.t, room temperature. hn.r, no reaction. iAgOCOCF2H,
in situ prepared by the reaction of Ag2CO3 and CF2HCOOH.
Scheme 2. Scope of the mono-difluoromethylation using standard reaction
conditions. Yields are isolated yield. 19F-NMR yields are given in parentheses.
a1 gram scale, AgNO3 0.2 equivalent and K2S2O8 2.5 equiv., 6 % of mono-C3-
CF2H as minor product was isolated, 22 % of starting material recovered.
bRatios are based on 19F-NMRs. c10 mol% of H2SO4 was added to standard
reaction condition (see SI).
Acetonitrile was found to be the optimum solvent. The use
of EtOH, MeOH, DCM, dioxane or DMF (Table 1, entries 7-11)
resulted in no reaction and a poor yield was obtained with acetone
(Table 1, entry 6). Attempts to use other oxidants than K2S2O8
t
such as BuOOH, H2O2 or (NH4)2S2O8 also afforded a poor yield
(Table 1, entries 12-15).
The use of different silver salts (Table 1, entries 16-19)
revealed that AgNO3 provided the highest yield. Other metals
Under the standard reaction conditions, difluoromethylation
of quinoline afforded the monosubstituted derivative 2-
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(difluoromethyl)quinoline as the dominant product (15, Scheme
2). In contrast, the use of DFMS resulted in formation of 2,4-
bis(difluoromethyl)quinoline.13 Noteworthy, during the synthesis
of compounds 2, 8 and 9 (Scheme 2), bis-difluoromethylated
products were observed in minor amounts. Encouraged by these
observations, we investigated if a one-step disubstitution of
quinoline could be accomplished using difluoroacetic acid as
reagent and AgNO3 as catalyst applying more forceful reaction
conditions. Indeed, increasing the reaction temperature to 70 °C
or slightly higher, successfully afforded 17 as the major product in
one-step from quinoline (mono-bis, 1:16, Scheme 3). Thus, the
present reaction not only enables selective monosubstitution but
intensified reaction conditions empower a one-step disubstitution.
With these new reaction conditions in hand, several
heteroaromatic systems were successfully bis-difluoromethylated
as listed in Scheme 4.
Noteworthy, the products arising from the bis-
difluoromethylation always contain one of the difluoromethyl
moieties at the C-2 position. In several cases (Scheme 4), small
amounts of the C-2 mono-difluoromethylated product were
observed along with bis-difluoromethylated product. In general,
the second difluoromethyl radical preferentially reacts with the
electron deficient carbon in the heteroaromatic ring. During the
bis-difluoromethylation of 4-methylquinoline, in which the C-4
position is blocked by a methyl group, the second difluoromethyl
group is installed at the C-8 (18, Scheme 4). Since C-8 is not an
electron deficient position, this represents an exception from the
general observed rules. This unexpected product might be formed
via reaction of the radical intermediate generated after the initial
reaction installing the first difluoromethyl moiety with a second
difluoromethyl radical. A study of the resonance structures of this
intermediate reveals that it is possible to rationalize a plausible
resonance structure with the radical at C-8.18 The assumption that
the second alkylation occurs by the reaction of an intermediate
formed after the first alkylation is supported by the observation
that compound 15 cannot be converted into 17 (Scheme 5)
whereas conversion of quinoline into 17 occurs smoothly by a
one-step reaction (Scheme 3). In addition, no reaction occurs
when blocking C-2 in the compounds tested (Scheme 5). Thus,
we believed that the introduction of the first difluoromethyl moiety
at C-2 under the reinforced reaction conditions (higher
temperature, > 70 °C) leads to formation of an intermediate, which
reacts with the second difluoromethyl radical affording formation
of the disubstituted product. Overall, the site-selectivity of second
difluoromethyl radical depends on availability of electron deficient
positions and the substitution pattern in the heteroaromatic ring.
Scheme 3. Controllability of the mono- and bis- difluoro-methylation of quinoline.
No tri-substitution/decomposition when temperature increasing to above 100 °C.
Boiling point of CF2HCOOH is 132-134 °C. aRatio is based on 19F-NMR.
Scheme 5. Limitation and mechanistic studies of mono/bis-difluoromethylation.
No reaction was observed when C-2 blocked.
Interestingly, in the case of ethyl 4-nicotinate, the second
difluoromethyl group was introduced into the electron deficient C-
5 position (compound 19) and not at C-6. Apparently, the electron
withdrawing effect of the carbonyl group overrules the directing
effects of the nitrogen on C-6. In the report by Fujiwara et al.[13]
2,6-difluoromethylation of isonicotinamide is the dominating
product when DFMS is used as the reagent. The different product
distribution indicates dissimilar reaction pathways. One
explanation could be that two independent alkylations occur when
using DFMS.[13] Using the present reactions conditions, the 2,6-
difluoromethylated product is only formed if the 3,5-
dimethylpyrazine was transformed to the corresponding bis-
difluoromethylated product (21) in a one-pot procedure.
Scheme 4. Scope of the one-step bis-difluoromethylation using standard
reaction conditions. Yields are isolated yield. aRatios are based on 19F-NMRs.
Mono-difluoromethylation occurs at the electron poor
carbon atom neighboring the nitrogen atom (Scheme 2)
indicating that a nucleophilic difluoromethyl radical reacts with the
heterocycles. This assumption also deliniates the substitution
pattern in the bis-difluoromethylated quinoline molecule, where
the second difluoromethyl group is attached to the electron
deficient (i. e. the C-4 position) to form 17 (Scheme 3).
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10.1002/chem.201704261
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2007, 317, 1881-1886; (d) R. Poulin; L. Lu; B. Ackermann; P. Bey; A. E.
Pegg, J. Biol. Chem. 1992, 267, 150-158.
Attempt to perform tri-substitution by increasing the reaction
temperature to above 100 °C solely resulted in decomposition
(Scheme 3).
Based on our observation and the recent mechanistic
studies,12g,12h,19,20 we propose the mechanism depicted in
Scheme 6 for mono-difluoromethylation of quinoline. Specifically,
we proposed that the formation of difluoromethyl radical is evoked
by silver-catalyzed oxidative decarboxylation of difluoroacetic
acid and subsequent addition to the heteroaromatic ring.
[4]
There are six other drugs containing CF2H: zardaverine, D0870, RS
71684, flucythrinate, foridon and devacoxib. However, It should be noted
that roflumilast, pantoprazole, zardaverine, RS 71684 and flucythrinate
are actually containing -OCF2H not carbon-bonded -CF2H.
N.A. Meanwell, J. Med. Chem. 2011, 54, 2529-2591.
[5]
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Scheme 6. Plausible mechanism for mono-difluoromethylation. Proposed
mechanism for mono-difluoromethylation of quinoline.21
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fluoroarylacetatic acids and α,α-difluoroarylacetic acids see: j) S. Mizuta,
I. S. R. Stenhagen, M. ODuill, J. Wolstenhulme, A. K. Kirjavainen, S. J.
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2015, 17, 38.
In conclusion, we have discovered that difluoroacetic acid
can be used as a new reagent for innate C-H difluoromethylation
of heteroaromatic compounds. The procedure presented is
technically simple, scalable, inexpensive, controllable and a direct
C-H activation synthetic methodology for preparation of both
mono- and bis-difluoromethylated derivatives of N-containing
heteroaromatics. Remarkably, the present protocol employs the
easily accessible and off-the-shelf difluoroacetic acid as starting
material. Furthermore, the late-stage one-step access to bis-
difluoromethylated products is novel and has enabled synthesis
of several compounds, which were not available using previously
reported reaction conditions. Since the protocol makes a broad
number of difluoromethylated derivatives of heteroaromatic
compounds available, this report enables preparation of previous
inaccessible tool compounds for biological assays and predictably
important lead structures for drug discovery. Intensive studies on
the mechanism as well as expanding the scope of this reaction
are currently being performed in our lab.
[13] Y. Fujiwara, J.A. Dixon, R.A. Rodriguez, R.D. Baxter, D.D Dixon, M.R.
Collins, D.G. Blackmond, P.S. Baran, J. Am. Chem. Soc. 2012, 134,
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Acknowledgements
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S. Baran, Nature. 2012, 492, 95-99; and references therein.
This work was supported by the University of Copenhagen
Excellency Program for Interdisciplinary Excellence (UC2016).
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Keywords: difluoromethylation • difluoroacetic acid • bis-
difluoromethylation • radicals
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[3]
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10.1002/chem.201704261
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
Truong Thanh Tung, Søren Brøgger
Christensen and John Nielsen*
Page No. – Page No.
Difluoroacetic Acid as a New
Reagent for Direct C-H
Difluoromethylation of
Heteroaromatic Compounds
A technically simple procedure for direct C-H difluoromethylation of heteroaromatic
compounds using off-the-shelf difluoroacetic acid as the difluoromethylating
reagent has been developed. Mono-difluoromethylation versus bis-
difluoromethylation is controlled as the result of the reaction temperature. The
reactions described here enable access to the late-stage C–H mono- and bis-
difluoromethylation for preparation of tool compounds for chemical biology and
provide access to this hitherto untapped substituent for drug discovery.
This article is protected by copyright. All rights reserved.