Sandmeyer difluoromethylation of (hetero-)arenediazonium salts

Article abstract of DOI:10.1021/ol5030037

A Sandmeyer-type difluoromethylation process has been developed that allows the straightforward conversion of (hetero-)arenediazonium salts into the corresponding difluoromethyl (hetero-)arenes under mild conditions. The actual difluoromethylating reagent, a difluoromethyl-copper complex, is formed in situ from copper thiocyanate and TMS-CF₂H. The diazonium salts are either preformed or generated in situ from broadly available aromatic amines.

Full text of DOI:10.1021/ol5030037

Letter
pubs.acs.org/OrgLett
Sandmeyer Difluoromethylation of (Hetero-)Arenediazonium Salts
Christian Matheis, Kevin Jouvin, and Lukas J. Goossen*
́
Department of Organic Chemistry, TU Kaiserslautern, Erwin-Schrodinger-Str. Geb. 54, 67663 Kaiserslautern, Germany
̈
S
* Supporting Information
ABSTRACT: A Sandmeyer-type difluoromethylation process has
been developed that allows the straightforward conversion of
(hetero-)arenediazonium salts into the corresponding difluoro-
methyl (hetero-)arenes under mild conditions. The actual
difluoromethylating reagent, a difluoromethyl−copper complex, is
formed in situ from copper thiocyanate and TMS−CF2H. The
diazonium salts are either preformed or generated in situ from
broadly available aromatic amines.
luorine-containing residues are central functionalities in
aryl bromides or chlorides catalyzed by Pd, followed by ketone
cleavage with KOH/H2O.8 Both these cleavage steps call for
rather harsh conditions.
Baran and co-workers disclosed a radical difluoromethylation
of heteroaromatic compounds with zinc difluoromethanesulfi-
nate Zn(SO2CF2H)2 that proceeds under mild conditions.
Unfortunately, the reaction has a limited scope and usually
leads to mixtures of regioisomers.9
In view of the high level of efficiency reached in the
analogous trifluoromethylations, one would have expected that
aryl electrophiles could be difluoromethylated with difluor-
omethyl copper complexes6e generated, e.g., from TMS−CF2H.
This difluoromethylating reagent is easily accessible by reducing
the Ruppert−Prakash reagent TMS−CF3 with NaBH4.10
However, TMS−CF2H is substantially less reactive than
TMS−CF3 due to the stronger Si−CF2H bond.6e,11 Moreover,
Cu−CF2H complexes easily decompose with formation of
1,1,2,2-tetrafluoroethane and cis-difluoroethylene.6g,12
1
Fpharmaceuticals, agrochemicals, and functional materials.
Currently, 30−40% of marketed agrochemicals and about 25%
of pharmaceuticals contain fluorine atoms. Whereas perfluor-
oalkyl chains induce higher lipophilicity and metabolic stability
to bioactive substances,2 the CF2H group is considered isosteric
and isopolar with the hydroxy group.3 It is weakly acidic and
possesses a hydrogen-bond-donating capability comparable to
that of OH and NH groups, but the molecule remains more
lipophilic. As a result, CF2H is often a beneficial substitute for
such groups in various classes of biologically active compounds.
Examples include thiazopyr, fluxapyroxad, deracoxib, eflorni-
thine, pantoprazole, and ZSTK474 (see Figure 1).1e,4
Despite these difficulties, Hartwig et al. have recently
disclosed a nucleophilic difluoromethylation of electron-rich
aryl and vinyl iodides with Cu−CF2H complexes generated
from excess TMS−CF2H and copper iodide.13 Qing and co-
workers have extended this method to electron-poor substrates
and heteroarenes, reducing the reaction temperature to room
temperature and the amount of TMS−CF2H to 2.5 equiv by
introducing phenanthroline as a ligand and using t-BuOK as the
base (Scheme 1).14 Prakash et al. have disclosed a similarly
efficient protocol based on copper iodide and n-Bu3SnCF2H.
DFT studies revealed that DMF strongly stabilizes the Cu−
CF2H intermediate.15
In the context of our work on late-stage trifluoromethyla-
tions,16 we have recently developed Sandmeyer-type17 trifluoro-
methylations18 and trifluoromethylthiolations.19 An analogous
approach would be highly attractive also for the synthesis of
difluoromethyl arenes, because it would be based on easily
Figure 1. Bioactive molecules containing CF2H groups.
Traditional approaches to the synthesis of difluoromethyl
arenes include the fluorination of benzylic C−H bonds and the
deoxo-gem-difluoromethylation of aldehydes with SF4 or
aminosulfur trifluorides (e.g., DAST, Deoxofluor).5 However,
these reactions suffer from poor functional group tolerance and
harsh reaction conditions.
Methods for the late-stage installation of difluoromethyl
groups into functionalized molecules are highly sought-after.
However, compared to the tremendous progress made in
trifluoromethylation technology,2a,6 difluoromethylations have
met with considerably less success. The advent of easily
handled difluoromethylation reagents has sparked new develop-
ments in this field. The first type, α-trialkylsilyl difluoroacetate
esters, can undergo Cu-catalyzed cross-coupling with aryl
iodides, followed by hydrolysis and decarboxylation.7 The
second, difluoromethyl phenyl ketone, can be α-arylated with
Received: October 13, 2014
© XXXX American Chemical Society
A
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Letter
a
Scheme 1. One-Step Difluoromethylation Strategies
Table 1. Optimization of the Reaction Conditions
entry
Cu-salt
base
solvent preform. time/temp yield (%)
1
2
3
4
5
6
7
8
9
CuSCN
Cs2CO3
MeCN
0.5 h, rt
<10
26
<10
15
39
28
46
58
73
71
0
″
″
″
″
CsF
KF
CsF
″
″
″
″
″
″
″
″
″
″
″
″
″
NMP
DMF
CuI
″
″
″
″
″
″
″
″
CuSCN
0.5 h, 80 °C
0.5 h, 40 °C
1 h, 40 °C
″
″
″
″
″
″
−
b
10
b
12
b
13
CuSCN
−
0
a
Reaction conditions: The Cu reagent was preformed by stirring 2.50
mmol of TMS−CF2H, 0.50 mmol of copper salt, and 1.50 mmol of
base in 1 mL of solvent at given temperature and for given time. 0.50
mmol of 1 in 1 mL of solvent was added dropwise at 0 °C and stirred
for 12 h at rt. Yields were determined by 19F NMR using
available, inexpensive aryl amines rather than costly aryl iodides
(Scheme 1).
b
trifluoroethanol as an internal standard. 1.25 mmol TMS−CF2H.
However, such a Sandmeyer difluoromethylation may be put
into practice only if a suitable Cu−CF2H complex could
efficiently be generated from TMS−CF2H and sufficiently be
stabilized to enter the reaction pathway outlined in Scheme
2.18a
lower temperatures or with shorter reaction times, the reaction
does not proceed to completion, and at higher temperatures,
the Cu−CF2H species starts to decompose (entries 5, 7, and 8).
Accordingly, the highest yield of 73% was obtained when
stirring CuSCN, CsF, and TMS−CF2H for 60 min at 40 °C,
then cooling down, adding the diazonium salt, and continuing
to stir the reaction mixture overnight at room temperature
(entry 9). Following this procedure, the amount of TMS−
CF2H could be reduced to 2.5 equiv without impacting the
reaction outcome (entries 9 and 10).
Scheme 2. Mechanistic Sketch for a Sandmeyer
Difluoromethylation
Control experiments revealed that the reaction does not
proceed without either copper or base (entries 12 and 13).
Having thus found an efficient protocol for the Sandmeyer
difluoromethylation, we next investigated its scope (Scheme 3).
Various difluoromethyl arenes were smoothly synthesized from
the corresponding arenediazonium tetrafluoroborates. The
products were mostly isolated in pure form and fully
characterized. Only for some particularly volatile compounds,
the yields could only be determined by 19F NMR, and the
identity by mass spectroscopy.
Both electron-withdrawing and -donating substrates gave
similarly high yields. However, the reaction seems to be
sensitive toward steric hindrance, since ortho-substituted
products (3, 5, 8, 19) were formed in somewhat lower yields
than their para-substituted analogues (2, 7, 18). Various
common functional groups, such as chloro, trifluoromethyl,
cyano, nitro, amino, amido, and even bromo substituents, were
tolerated, the latter opening up opportunities for further
derivatization. Heteroarene diazonium salts including quino-
lines, carbazole, and indole derivatives were also difluoromethy-
lated in reasonable yields (23, 24, 25, 27). Arenediazonium
salts bearing carboxylate or iodo substituents were the sole
substrates giving unsatisfactory yields. In each case, large
amounts of unwanted protodediazotation products were
formed. Diazonium salts bearing keto groups (18, 19, 22)
were selectively difluoromethylated at the arene ring.
Protodediazotation was the main side reaction; nucleophilic
addition of the difluoromethyl group to the carbonyl group was
observed only in traces. Remarkably, the latter reaction took
place quantitatively for compound 21, and the difluoromethyl
alcohol was isolated in high yield.11,21
In order to probe the viability of this approach, we chose the
reaction of 4-methoxybenzenediazonium tetrafluoroborate (1)
with TMS−CF2H as a model and applied the conditions that
had been most efficient in the corresponding trifluoromethyla-
tion. However, the desired product was obtained only in very
low yield when slowly adding the diazonium salt to a solution
of CuSCN, Cs2CO3, and TMS−CF2H in MeCN that had been
prestirred for 30 min at room temperature (Table 1, entry 1).
Further investigations revealed that, in comparison to Cu−CF3,
the formation of Cu−CF2H species requires stronger bases,
which, however, negatively affect the subsequent Sandmeyer
process. With fluoride bases, and CsF in particular, the Cu−
CF2H preformation step became more efficient, so that the
overall yield of the process increased (entries 1−3). Changing
the reaction solvent to DMF further increased the yields, which
is in agreement with the studies by Prakash et al. that this
solvent stabilizes Cu−CF2H species (entries 2, 4, and 5).15
NMR studies of the mixture of CuSCN, TMS−CF2H, and CsF
in DMF confirmed that, under these conditions, Cu−CF2H
species are formed in high yields.20
Among the copper sources tested, copper thiocyanate gave
the best results (entry 5). In contrast, copper iodide, which has
been used in difluoromethylations of aryl iodides,13,15 led to
unwanted Sandmeyer halogenation (entry 6).
The decisive parameters turned out to be the Cu−CF2H
preformation duration and temperature. In situ NMR studies
revealed that this step requires 60 min at 40 °C (entry 9). At
B
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a
radical quenchers such as 2,2,6,6-tetramethylpiperidine-N-oxyl
(TEMPO) or p-benzoquinone are present, the reaction is
completely suppressed.22 Moreover, in the difluoromethylation
of 2-(allyloxy)diazonium tetrafluoroborate (28), the cyclized
product 29 was obtained (Scheme 5). These results, which
Scheme 3. Scope of the Sandmeyer Difluoromethylation
Scheme 5. Confirmation of Radical Pathway
confirm that the reaction proceeds via a radical mechanism, are
in good agreement with related studies for other Sandmeyer-
type reactions and support the mechanistic outline given in
Scheme 2.18a,19,23
In conclusion, a Sandmeyer-type difluoromethylation of
diazonium salts has been developed that opens up an expedient
synthetic entry to valuable difluoromethyl arenes and
heteroarenes from easily available aromatic amines. The key
advantages of the new process are its mild reaction conditions
and the fact that the difluoromethylating reagent can be
generated in situ from readily available precursors.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectral data for the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: goossen@chemie.uni-kl.de.
Notes
The authors declare no competing financial interest.
a
Reaction conditions: The Cu-reagent was preformed by stirring 2.50
mmol of TMS−CF2H, 1.00 mmol of CuSCN and 3.00 mmol of CsF
in 2 mL of DMF at 40 °C for 1 h. 1.00 mmol of Arenediazonium
tetrafluoroborate in 2 mL of DMF was added dropwise at 0 °C and
stirred for 12 h at rt. Yields of isolated products are given. bYields were
determined by 19F NMR using trifluoroethanol as an internal standard.
cStarting from 3-acetylbenzenediazonium tetrafluoroborate.
ACKNOWLEDGMENTS
We thank Nicolas Servely (TU Kaiserslautern) for technical
■
assistance, Kathe Gooßen (TU Kaiserslautern) for help with
̈
the manuscript, and NanoKat for financial support.
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