Mild chlorodifluoroacylation of indoles via self-activation of sodium chlorodifluoroacetate

Article abstract of DOI:10.1021/ol501854q

A mild acylation of N-alkylindoles is reported using sodium chlorodifluoroacetate (SCDA) to synthesize useful chlorodifluoroketones. Friedel-Crafts reactivity of carboxylate salts is unusual and is not observed in similar electron-deficient acetate salts such as sodium trifluoroacetate. Mechanistic experiments indicate that the characteristic ability of SCDA to generate difluorocarbene is responsible for the reaction pathway via self-activation to form the active ester.

Full text of DOI:10.1021/ol501854q

Letter
pubs.acs.org/OrgLett
Mild Chlorodifluoroacylation of Indoles via Self-Activation of Sodium
Chlorodifluoroacetate
Thomas J. Williams and Michael F. Greaney*
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, U.K.
S
* Supporting Information
ABSTRACT: A mild acylation of N-alkylindoles is reported using sodium
chlorodifluoroacetate (SCDA) to synthesize useful chlorodifluoroketones.
Friedel−Crafts reactivity of carboxylate salts is unusual and is not observed in
similar electron-deficient acetate salts such as sodium trifluoroacetate.
Mechanistic experiments indicate that the characteristic ability of SCDA to
generate difluorocarbene is responsible for the reaction pathway via self-
activation to form the active ester.
here is considerable interest in the development of new
Table 1. Chlorodifluoroacylation of 1,2-Dimethylindole
T
methods for selective incorporation of fluorine into
organic compounds. Fluorine-containing compounds play a
central role in pharmaceuticals (e.g., best-selling drugs
rosuvastatin, Advair, and sitagliptin), agrochemicals (e.g.,
fungicides epoxiconazole and flusilazole), and medical imaging
agents (18F positron emission tomography), with introduction
of the fluoro or perfluoro group frequently being the key
determinant to a viable synthesis.1
a
entry
salt (equiv)
base
yield of 3 (%)
1
2
3
4
5
6
2
CsF
NaF
51
Sodium chlorodifluoroacetate (SCDA, 1) is a versatile
reagent for introducing CF2 and CF3 groups in this regard.
The reagent undergoes decarboxylation at moderate temper-
atures (ca. 90 °C) to form difluorocarbene.2 This highly
reactive and transient intermediate can then be used in situ for
di- and (in the presence of fluoride base) trifluoromethyla-
tions.3,4 Unlike many common perfluoromethylating agents,
SCDA is an inexpensive, crystalline solid which is stable at
ambient temperature and in air.5 These factors have brought
the reagent into focus as a potential solution to process-scale di-
and trifluoromethylation.
We have recently reported S-, N-, and Se-difluoromethylation
methodologies using SCDA.6 In the course of these studies, we
uncovered a surprising result upon treatment of indole
derivatives with SCDA. Reaction of 1,2-dimethylindole 2a
with SDCA and CsF in DMF at 90 °C afforded the unexpected
chlorodifluoroacylated product 3a with moderate conversion
(Table 1). The connectivity of this product was confirmed by
2D NMR spectroscopy and XRD crystallographic studies
(Figure 1) on a subsequent derivative (vide infra). Trace
quantities of dimethylindole-3-carboxaldehyde were also
observed, presumably from the reaction of indole and DMF
in a Vilsmeier−Haack-type process.7
2
50
0.5
1
7
18
2
69 (57)
5
95 (81)
b
7
2
34
0
c
8
d
2
9
2
NEt3
NEt3
91
0
e
10
2
f
11
2
0
a
1
NMR yields calculated by H NMR spectroscopy. Isolated yields in
parentheses. Reaction performed in NMP solvent at 130 °C.
Reaction performed with chlorodifluoroacetic acid (CDA). Reaction
performed with CDA in the presence of triethylamine base (2 equiv).
Reaction performed with TFA. Reaction performed with TFA in the
b
c
d
e
f
presence of triethylamine base (2 equiv).
combined with the synthetic utility of chlorodifluoroke-
tones9−11 and chlorodifluoroalkylindoles,12 encouraged us to
investigate the reaction further.
An initial screen of reaction parameters established that base
was not required for the reaction but that SCDA stoichiometry
was very important (Table 1, entries 1−5). A minimum of 2
equiv was required for good yields (entry 5), with 5 equiv
providing an 81% isolated yield of 3a (entry 6). Substituting
SCDA for the protonated chlorodifluoroacetic acid shut down
Although Freidel−Crafts acylation of indoles at the 3-
position is well-known, it generally requires strong electrophiles
(anhydrides or acid chlorides) in combination with reactive
Lewis acids.8 Carboxylate salts are generally not considered to
be effective electrophiles, and to our knowledge, this is the only
example both of acylation of an indole with such a reagent and
of SCDA behaving in this reaction mode. These considerations,
Received: June 26, 2014
© XXXX American Chemical Society
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The unusual acylation reactivity of SCDA when compared
with other, similar, acetates rules out a simple electrophilic
substitution mechanism. Rather, the unique facility of SCDA to
generate difluorocarbene is likely implicated in the reaction
pathway. To investigate this possibility, we conducted the
reaction in the presence of the carbene traps 1-methoxy-4-
vinylbenzene15 and thiophenol (Scheme 2). The first reaction
Scheme 2. Carbene Trapping Experiments
Figure 1. XRD crystallographic structure for 3g (thermal elipsoids set
at 50%).
the reaction completely (entry 8), but on addition of
triethylamine the reaction proceeded to full conversion (entry
9). Finally, a control reaction using trifluoroacetic acid showed
no reactivity for both the acid and carboxylate (entries 10−11).
Additional control experiments with sodium trifluoroacetate,
pivalate, and acetate also gave no reaction.
With an optimized procedure in hand, we elected to first
examine the substrate scope of the process (Scheme 1). The
Scheme 1. Substrate Scope
reduced the reaction conversion to 46%, but only trace
quantities of difluorocyclopropane 5 were observed by 19F
NMR spectroscopy. The second reaction, however, showed
suppression of acylation and a 72% conversion (determined by
19F NMR spectroscopy) to PhSCF2H (7) with 2 equiv of
SCDA.6,16 Taken with the stoichiometric requirement for two
equivalents of SCDA in the reaction, we propose the self-
activating mechanism shown in Scheme 3. Decomposition of
Scheme 3. Proposed Mechanism
reaction was found to be entirely selective for the indole 3-
position when the 2-methyl group was removed (3b).13
Electron-donating substitution on the benzo-fused ring
generally gave good to excellent yields of the acylated products
(3f,g).14 Electron-withdrawing substituents, by contrast, were
poorly tolerated in the reaction, e.g., 1-methyl-5-nitroindole was
entirely unreactive. Similarly, attenuation of the indole
nucleophilicity at the N-position in the form of Ts or Boc
groups shut down the reaction. However, an electron-donating
N-benzyl group gave the product in excellent yield (3h).
SCDA generates difluorocarbene, which may be trapped by a
molecule of the starting carboxylate. The activated ester 8 then
enables Friedel−Crafts acylation of indole in the usual manner.
To test this hypothesis, we carried out a mixed activation
experiment. As discussed above, substituting SCDA with
NaTFA does not give the corresponding trifluoroacylindole
product, as NaTFA cannot decompose to give difluorocarbene
B
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and hence cannot generate an active ester of type 8. However,
in the presence of SCDA (i.e., a reaction regime which can
produce difluorocarbene and ester 8) 32% of 9 is observed,
along with a trace quantity of 3a.
The chlorodifluoroacyl group is a valuable synthon for the
construction of vic-difluorinated molecules. To demonstrate the
potential of this simple chlorodifluoroacylation method for the
synthesis of more complex fluoro-organics, we carried out a
selection of transformations shown in Schemes 4 and 5.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: michael.greaney@manchester.ac.uk.
Notes
Scheme 4. Reaction with O-Nucleophiles
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the EPSRC for funding. Mr. Gareth Smith
(University of Manchester) is thanked for mass spectrometry.
Dr. T. E. Storr (University of Manchester) is thanked for
crystallography.
REFERENCES
■
Scheme 5. Further Transformations of CF2Cl
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