Transition-metal-free trifluoromethylthiolation of n-heteroarenes

Article abstract of DOI:10.1002/chem.201500957

A general and efficient methodology for the direct transition metal free trifluoromethylthiolation of a broad range of biologically relevant N-heteroarenes is reported employing abundant sodium chloride as the catalyst. This method is operationally simple, exhibits high functional group tolerance, and does not require protecting groups. A pinch of salt: A general and efficient methodology for the direct transition-metal-free trifluoromethylthiolation of a broad range of biologically relevant N-heteroarenes is reported employing abundant sodium chloride as the catalyst. This method is operationally simple, exhibits high functional group tolerance, and does not require protecting groups.

Full text of DOI:10.1002/chem.201500957

DOI: 10.1002/chem.201500957
Communication
&
Heterocycles
Transition Metal-Free Trifluoromethylthiolation of N-Heteroarenes
[
a]
Roman Honeker, Johannes B. Ernst, and Frank Glorius*
focused on the trifluoromethylthio group (CF S), due to its
3
Abstract: A general and efficient methodology for the
direct transition metal free trifluoromethylthiolation of
a broad range of biologically relevant N-heteroarenes is
reported employing abundant sodium chloride as the cat-
alyst. This method is operationally simple, exhibits high
functional group tolerance, and does not require protect-
ing groups.
electron-withdrawing effect and high lipophilicity, which can
improve metabolic stability and the transmembrane permea-
[2,3]
tion of drugs, respectively.
Different strategies have been
developed over the years to incorporate the trifluoromethylth-
[4]
io group into molecules. Traditional methods, such as, tri-
[5]
fluoromethylation of sulfur-containing compounds, halogen–
[
6]
[7]
fluorine exchange reactions, and coupling of halides or bor-
[8]
onic acids, require prefunctionalized substrates. Alternatively,
the direct transformation of a CÀH bond into a CF S group ap-
3
pears to be the most efficient and practical synthetic approach
towards trifluoromethylthiolated heteroarenes. Recently, tri-
fluoromethylthiolation of heteroarenes by means of CÀH acti-
vation were reported, however directing groups were re-
N-Heteroarenes comprise the core structure of numerous natu-
[
1]
ral products, pharmaceuticals, and agrochemicals. The choles-
terol-lowering Atorvastatin (Lipitor) and the GABAA receptor
agonist Zolpidem are prominent examples of bioactive com-
pounds containing an N-heteroaromatic core (Figure 1). In this
context, the development of efficient and selective methods
for the functionalization of N-heterocycles such as pyrroles, in-
doles, and related ring systems is highly desirable.
[9]
quired. Early work in the field of electrophilic trifluorome-
thylthiolation employed gaseous trifluoromethylsulfenyl chlo-
ride (CF SCl) as an electrophilic reagent. However, its high tox-
3
[10]
icity and corrosive properties limit its use. Recently, shelf-
stable electrophilic CF S reagents have been developed, in
3
part also to avoid handling of CF SCl (Figure 2).
3
Figure 1. Examples of N-heteroarenes in pharmaceutical chemistry.
Incorporation of fluorinated functionalities is an important
strategy to improve the properties of bioactive compounds in
[
2]
the pharmaceutical and agrochemical fields. Thus, new effi-
cient catalytic methods for the introduction of fluorinated moi-
eties to diverse molecules are highly desirable. Furthermore,
transformations must be robust and broadly applicable since
high-throughput experimentation is frequently applied in
these fields. Due to the strict restrictions concerning the metal
contamination of drugs, transition metal-free procedures are
particularly attractive. In this context, much attention is being
Figure 2. Shelf-stable electrophilic trifluoromethylthiolation reagents.
These reagents have been shown to require a catalyst/acti-
vator for the direct CÀH functionalization of heteroarenes. Im-
portantly, the type of catalyst/activator significantly influences
the general applicability of the transformation and its function-
[11]
[12]
[8f,13]
al group tolerance. Reagents 1a, 1b, and 2
(Figure 2)
+
+
[
a] R. Honeker, J. B. Ernst, Prof. Dr. F. Glorius
Organisch-Chemisches Institut
were reported to be activated by Brønsted or Lewis acids pre-
venting their application for the trifluoromethylthiolation of
pyrroles due to their sensitivity towards polymerization under
Westfꢀlische Wilhelms-Universitꢀt Mꢁnster
Corrensstraße 40, 48149 Mꢁnster (Germany)
E-mail: glorius@uni-muenster.de
[11b]
acidic conditions.
Comparable limitations are valid for re-
+
agent 3, which is known to require Lewis acids, so few struc-
[
] Authors contributed equally.
turally or electronically specific pyrrole derivatives could be tri-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500957.
[14]
fluoromethylthiolated by employing this reagent.
For re-
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agent 4, copper salts were reported to be effective in activa-
acetamide, DMF, and DMSO), with DMF (p.a. grade) giving the
most consistent results. Therefore, DMF was chosen as the op-
timal solvent.
tion, however high catalyst loadings of the transition metal
[
15]
were required.
To address the demands for synthetic procedures made by
the pharmaceutical and agrochemical fields, we envisaged the
development of a transition metal-free method for trifluorome-
thylthiolation that is robust, operationally simple, and generally
applicable to pyrroles, indoles, and related heteroarenes. We
With the optimized conditions in hand, we next investigated
the scope of the reaction. Electronically and structurally diverse
pyrrole derivatives were selectively converted into the desired
trifluoromethylthiolated products in excellent yields employing
[16]
chose compound 5 (Figure 2) as the electrophilic reagent,
due to its high stability and ease of synthesis, as reported by
[
8d]
Rueping and co-workers. Additionally, to date, this reagent
has not been applied in the CÀH functionalization of heteroar-
enes. Employing 2-phenylpyrrole (6a) as the model substrate,
we initially attempted the reaction without catalyst. However,
the desired product was only formed in trace amounts
(Table 1, entry 1). We therefore commenced searching for a cat-
[
a]
Table 1. Catalyst screening.
[
b]
Entry
Catalyst
Yield [%]
1
2
3
4
5
6
7
8
9
–
KF
NaI
KI
LiBr
NaBr
KBr
LiCl
NaCl
KCl
trace
trace
trace
trace
60
52
24
85
94
1
0
89
11
NBu
4
Cl
92
Scheme 1. Trifluoromethylthiolation of pyrrole derivatives. Reaction condi-
tions (unless otherwise stated): Pyrrole (0.5 mmol), reagent 5 (1.0–1.1 equiv),
sodium chloride (10 mol%), DMF (2.5 mL), 14 h, 908C. DMF=dimethylforma-
mide. Yields of isolated product are given. [a] 1.3 equivalents of 5. [b] Pyrrole
[
a] Reaction conditions: Pyrrole 6a (0.1 mmol), reagent 5 (1.1 equiv), cata-
lyst (10 mol%), DMA (0.5 mL), 908C, 3 h; [b] GC yield. DMA=dimethylace-
tamide.
(
0.1 mmol), DMF (0.5 mL), 24 h.
alyst that was effective at activating reagent 5 and, most im-
portantly, still compatible with highly sensitive pyrroles. Based
on previous reports on the activation of thiophthalimide re-
only a slight excess of the reagent 5 (Scheme 1). The reaction
was observed to exhibit a broad functional group tolerance.
Aliphatic as well as electronically diverse aryl substituents were
well tolerated (Scheme 1, 7a–f). Furthermore, substrates bear-
ing different carbonyl groups (ketone, aldehyde, ester and
amide) attached directly to the pyrrole core were efficiently tri-
fluoromethylthiolated (Scheme 1, 7d–g). Importantly, the reac-
tion did not require a protecting group on the pyrrole nitro-
gen. However, aliphatic, benzylic, and electronically diverse ar-
omatic substituents at the nitrogen atom were tolerated
(Scheme 1, 7g–l), which is significant as N-substituted pyrroles
[
17]
agents by halide ions, we investigated different halide sour-
ces as catalysts. Fluoride and iodide sources showed no cata-
lytic activity (Table 1, entries 2–4), whereas product formation
in low to moderate yields was observed on employing bro-
mide sources (Table 1, entries 5–7). To our delight, alkali chlor-
ides were very effective for this transformation (Table 1, en-
tries 8–10), with sodium and potassium chloride as the most
active catalysts, despite previous reports that they were cata-
[
17a]
lytically inactive.
To rule out catalysis by the alkali cation,
[1a]
the reaction was performed with tetrabutylammonium chloride
as catalyst, also leading to an excellent yield (Table 1, entry 11;
see the Supporting Information for more results). We chose
sodium chloride as a very cheap and effective catalyst for fur-
ther reactions. Undertaking solvent screening, the reaction oc-
curred only in very polar solvents (similar yields in dimethyl-
represent core structures in many natural products and bio-
[1e]
active compounds.
Next, we applied our procedure to the trifluoromethylthiola-
tion of indoles in order to examine the generality of our
method. Gratifyingly, a broad range of indole derivatives could
be converted to the desired products in excellent yields
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Communication
Scheme 3. Trifluoromethylthiolation of different N-heteroarenes. Reaction
conditions: Heteroarene (0.5 mmol), reagent 5 (1.1 equiv), sodium chloride
(
10 mol%), DMF (2.5 mL), 908C, 14 h. Yields of isolated product are given.
thylthiolation of imidazo[1,2a]pyridine, which represents an im-
[20]
portant class of drugs acting as GABAA receptor agonists.
giving product 12.
To elucidate the mechanistic aspects of the transformation,
we first carried out the trifluoromethylthiolation of indole in
the presence of radical inhibitors (Scheme 4). In the case of hy-
droquinone and 2,6-di-tert-butyl-4-methylphenol (BHT), no in-
Scheme 2. Trifluoromethylthiolation of indole derivatives. Reaction condi-
tions (unless otherwise stated): Indole (0.5 mmol), reagent 5 (1.1 equiv),
sodium chloride (10 mol%), DMF (2.5 mL), 908C, 24 h. Yields of isolated
2
product are given. [a] reaction time=14 h. [b] PdCl (5 mol%) as catalyst.
(
Scheme 2). Again, no protecting group was required and both
Scheme 4. Trifluoromethylthiolation of indole in the presence of radical in-
hibitors. Reaction conditions: indole (0.1 mmol), reagent 5 (1.1 equiv),
electron-withdrawing (Scheme 2, 9c–h) and electron-donating
substituents (Scheme 2, 9i) were well tolerated. Notably, substi-
tution of the benzo moiety, in any position, did not negatively
influence the reaction (Scheme 2, 9c–i). However, whereas a 2-
substituted indole was smoothly converted to the desired
product (Scheme 2, 9b), no product was observed in the case
of 3-substituted indole derivatives. Since the latter represent
an important structural motif in pharmaceuticals and natural
sodium chloride (10 mol%), radical inhibitor (0.5 equiv), DMF (0.5 mL), 908C,
19
1
4 h. Yields were determined by F NMR spectroscopy with (trifluorome-
thoxy)benzene as internal standard.
fluence on the yield of the reaction was observed, whereas
free radicals, namely 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) and galvinoxyl, led to diminished yields. However, no
radical coupling products were observed. These results, com-
bined with the observed C3-selective functionalization of in-
doles, indicate an electrophilic substitution mechanism rather
than a radical pathway.
[
1b–e]
products,
we conducted a brief screening of chloride sour-
ces with other metal cations for the additional activation of
the indole core. To our delight, palladium(II) chloride and
gold(III) chloride both displayed high catalytic activities. Thus,
employing palladium(II) chloride as the catalyst, under other-
wise identical conditions, 3-methylindole (Scheme 2, 8k) and
ethyl-3-indole-acetate (Scheme 2, 8l) were converted to the
desired trifluoromethylthiolated compounds. The latter repre-
sents a derivative of indole-3-acetic acid (IAA), a naturally oc-
curring phytohormone that, along with its derivatives, is used
[17a,21]
In light of previous reports,
we propose that catalytic
amounts of chloride acting as a Lewis base lead to the in situ
formation of highly reactive trifluoromethylsulfenyl chloride
(CF SCl). The latter subsequently undergoes an electrophilic ar-
3
omatic substitution reaction with the N-heteroarene, yielding
[10a]
the desired trifluoromethylthiolated product (Scheme 5).
Monitoring the trifluoromethylthiolation of 2-phenylpyrrole
[
18]
in the agrochemical field.
19
Finally, we turned our attention to the trifluoromethylthiola-
tion of more challenging N-heteroarenes (Scheme 3). To our
delight, 7-azaindole and an indolizine derivative provided the
desired products (10, 11) in excellent yields. Both heteroarenes
constitute important classes of bioactive compounds. Fur-
thermore, we successfully performed the selective trifluorome-
by F NMR spectroscopy (470 MHz, [D ]DMSO), we observed
6
the continuous decrease of the signal from reagent 5 (d=
À48.4 ppm), whereas the signal from the product (d=
À44.6 ppm) increased. However, neither CF SCl nor any related
3
[19]
intermediate were detected, which may be attributed to its
high reactivity. Repeating the reaction in the absence of 2-phe-
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Communication
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3
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trifluoromethylthiolation of a range of diverse biologically rele-
vant N-heteroarenes was developed, employing sodium chlo-
ride as a cheap and simple catalyst. The transformation is
robust and exhibits a broad functional group tolerance. Thus,
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1
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Published online on && &&, 0000
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COMMUNICATION
A pinch of salt: A general and efficient
methodology for the direct transition
metal-free trifluoromethylthiolation of
a broad range of biologically relevant N-
heteroarenes is reported employing
abundant sodium chloride as the cata-
lyst. This method is operationally
simple, exhibits high functional group
tolerance, and does not require protect-
ing groups.
&
Heterocycles
R. Honeker, J. B. Ernst, F. Glorius*
& – &&
&
Transition Metal-Free
Trifluoromethylthiolation of N-
Heteroarenes
&
&
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!