An aryne triggered ring-opening fluorination of cyclic thioethers with potassium fluoride

Article abstract of DOI:10.1039/c8cc03766c

Herein, we report an aryne triggered ring-opening fluorination protocol of a great variety of saturated sulfur heterocycles. A key factor for the success is the identification of a suitable mediator. Compared to previous methods, this transition-metal free protocol employs low-cost potassium fluoride as the fluorine source. The operational simplicity and mild reaction conditions allow for the rapid synthesis of a wide range of aliphatic fluoride compounds in good yields.

Full text of DOI:10.1039/c8cc03766c

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
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An aryne triggered ring-opening fluorination of cyclic thioethers
with potassium fluoride
Rong Fan,a Binbin Liu,a Tianyu Zheng,a Kun Xu*b, Chen Tan,a Tianlong Zeng,a shuaisong Sua and
Jiajing Tan*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Abstract: Herein, we reported an aryne triggered ring-opening component aryne mediated ring-opening reaction of cyclic
fluorination protocol of
great variety of saturated sulfur thioethers.7 The sulfonium species formed in situ could
a
heterocycles. A key factor for the success is to identify a suitable deprotonate the pre-nucleophiles, which subsequently
mediator. Compared to previous methods, this transition-metal attacked the activated carbon-sulfur bond to provide the ring-
free protocol employs low-cost potassium fluoride as the fluorine opening products (Scheme 1a). During this project, the authors
source. The operational simplicity and mild reaction conditions questioned if fluorides required for aryne generation could be
allow for the rapid synthesis of a wide range of aliphatic fluoride also utilized to open the ring as the nucleophile. From a
compounds in good yields.
conceptual standpoint, our idea ought to be challenging, as
literature studies revealed that the high electronegativity and
low polarizability of fluoride often made itself a less reactive
nucleophile but relatively strong base in organic reactions.8
Fluorinated organic compounds has recently emerged as the
major focus in medicinal, agrochemical and materials
chemistry field, as fluorine atoms could create a variety of
unique properties.1 For instance, the installment of fluorine
atoms into pharmaceutical candidates can significantly
improve their metabolic stability, lipophilicity, and overall
bioactivity.2 Fluorine could be also employed as biochemical
probes to study biological processes via the in vivo magnetic
resonance imaging of the 19F nuclei.3 Consequently, significant
research efforts toward the invention of novel fluorination
reaction has been witnessed during the past two decades.4
While many protocols focus on the Csp2-F bond formation, the
synthetic method to enable Csp3–F bond formation is still
relatively underdeveloped.5 Moreover, available methods
often suffered from high cost and poor atom economy of
fluorine source. In this case, developing alternative aliphatic
fluoride synthesis protocol that employs readily available,
inexpensive fluorine source remains an elusive task in organic
synthesis.
Scheme 1. Working hypothesis
To this end, we proposed that the utilization of a mediator
involving a transferable proton is necessary. The reactivity of
the mediator must be “tailor-made” that besides being a
proton donor to capture the ylide intermediate to form the
key sulfonium ion, the deprotonated form of mediators would
neither react with aryne directly, nor enable the competing
ring-opening reaction as nucleophiles (Scheme 1b).9 Due to the
lower nucleophilicity of fluoride, side reactions including the
ring-opening polymerization, decomposition of sulfonium
intermediates as well as ring contraction also needed to be
minimized or even obviated.10 As such, a critical feature of this
proposed transformation would be the identification of
suitable mediators. Despite these challenges, we herein would
like to report our recent efforts in developing an aryne
triggered ring-opening fluorination reaction of cyclic thioethers
Aryne chemistry has undergone a renaissance in recent
years. As highly electrophilic species, arynes readily react with
a great variety of nucleophiles to build molecule complexity in
high efficacy.6 Recently, our group disclosed
a three-
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(four to six membered), which employs readily available fluorinated products 4b
Journal Name
-
4e in 70-82% yields. Substrates with
potassium fluoride (KF). Given the importance of all-carbon quaternary center at 4-position were also viable
organofluorine compounds, this transition metal-free that 4f and 4g proceeded in 69% and 74% yield, respectively.
transformation should be of great interests to the community.
Furthermore, substrates bearing cyclic ketal moiety underwent
We began our investigation by exploring the suitable the desired ring opening reactions smoothly to give
mediator in the model reaction of 2-(trimethylsilyl)aryl triflate corresponding products 4h and 4i. It is noteworthy that even
(
1a) and thietane (2a) in tetrahydrofuran with KF/18-C-6 as the the azetidinyl spirothietane proved to be viable substrate to
fluoride source (Table 1). To our delight, the desired product afford the fluorinated product 4j in 90% yield, while the
4a was obtained in 57% yield in the presence of water, which medicinally relevant azetidine moiety kept intact. We believed
confirmed our working hypothesis mentioned above (entry 1). that this result could be rationalized by the change in
Next, a series of well-designed mediators were thus examined nucleophilicity between thietane and its nitrogen analogue.
(entries 2-8). The experimental results revealed that 2,3- When tetrahydrothiophene and thiane were subjected to the
dimethylindole was superior to give the desired fluorinated reaction conditions, both of which formed the desired
product 4a in 80% yield (entry 7), while other additives gave fluorinated sulfide products (4k-4l). As might be expected, the
inferior results (entries 2-6). The critical role of 2,3- diminished yield and elevated reaction temperature were
dimethylindole was further demonstrated by the trace observed, which are probably due to their reduced ring strain.
fluorinated product obtained, when the control reaction was Under standard reaction conditions, the reaction of 2-
performed without the utilization of mediators (entry 8). methyltetrahydrothiophene 2m gave exclusively the
Lowering or increasing the reaction temperature proved to be elimination products 4m and 4m’ in 70% total yield with 1:4
detrimental, leading to decreased chemical yields (entries 9- ratio of regioisomers, demonstrating a limit of our protocol.
12). When tetrabutylammonium fluoride (TBAF) or cesium
fluoride (CsF) was utilized as the fluoride source instead, only Table 2. Substrate Scopea,b
trace amount of desired product was observed under
otherwise identical reaction conditions (entries 13-14).
Table 1. Reaction Condition Optimizationa
Fluoride
source
Temp Yield(
.(oC)
Entry
Mediator
%)b
1
KF/18-C-6
KF/18-C-6
KF/18-C-6
KF/18-C-6
KF/18-C-6
H2O
MeOH
i-PrOH
TTBP
0
57
2
0
64
67
3
0
4c
5
0
70
carbazole
0
68
6
KF/18-C-6 tetrahydrocarbazole
KF/18-C-6 2,3-dimethylindole
0
66
7
0
80
8
KF/18-C-6
None
0
Trace
67
9
KF/18-C-6 2,3-dimethylindole
KF/18-C-6 2,3-dimethylindole
KF/18-C-6 2,3-dimethylindole
KF/18-C-6 2,3-dimethylindole
-10
10
11
12
13
10
30
50
0
60
52
25
TBAF
CsF
2,3-dimethylindole
2,3-dimethylindole
Trace
Trace
14d
0
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), KF (0.7
mmol), 18-Crown-6 (0.7 mmol), THF (2 ml), mediator (0.5
b
mmol, stirring for
Determined by 1H NMR using an internal standard. 48h
5 minutes before adding), 24h.
c
d
instead of 24h.
butylphenol.
Solvent: CH3CN. TTBP: 2,4,6-Tri-tert-
a
b
Isolated yields. 1a (0.2 mmol), 2,3-dimethylindole (0.5
mmol), sulfur heterocycles (0.3 mmol), KF/18-C-6 (0.7
mmol), THF (2 mL) for 24 h at 0 oC. c KF/18-C-6 (0.14 mmol),
48 h. d Determined by 1H NMR spectroscopic analysis.
By using the optimal fluorination reaction conditions
described in Table 1, we explored the fluorination of a wide
range of cyclic thioethers. As shown in Table 2, thietanes
containing phenyl, benzyl and allyl substituent groups were all
tolerated well under the optimized reaction conditions, giving
We next turned our attention to determining the scope of
aryne components that are amenable to this fluorination
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reaction. As shown in Table 3, symmetric aryne precursors that mechanism of this ring opening protocol, the deuterium-
incorporate various functional groups are readily tolerated, labeling experiment was carried out (Scheme 4b). Consistent
affording the ring-opening fluorinated products (5a-5d) in with the proposed mechanism, the reaction proceeded in the
good yields and great structural diversities. In general, arynes presence of D2O to give the fluorinated product 4a-D in 50%
bearing electron-withdrawing groups gave less satisfying yield and 99% deuterium incorporation at the ortho-position of
results than those with electron-donating groups. When the alkyl chain.
unsymmetrical arynes were employed, the reactions
proceeded as expected to give the corresponding products 5e
-
5h in moderate yields although with poor regioselectivities.
These observations were in accordance with the weak-biasing
effects observed in previous reports.11 It’s important to note
that 3-methoxy substituted benzyne gave ring-opening
fluorinated product 5i and 5i’ with a 9:1 ratio, which could be
rationalized by the distortion/interaction model disclosed by
Garg and Houk.12
Table 3. Substrate Scopea,b
Scheme 4. Synthetic applications and D-labeling experiment
In conclusion, we successfully developed an aryne-triggered
ring opening fluorination reaction with the aid of a “tailor-
made” mediator. The operational simplicity and mild reaction
conditions enable the synthesis of a diverse collection of
valuable fluorinated products in good yields. Remarkably, this
transition-metal free protocol proved to be not only scalable,
but also easily possible for further functionalization. Given the
importance of fluorine-containing compounds, we anticipate
this method will find broad application in both the academic
and industrial settings.
JJT is grateful to the support by National Natural Science
Foundation of China (21702013), Beijing Natural Science
Foundation (2184115) and the Fundamental Research Funds
from the Central Universities (buctrc201721 and PYCC1707) in
Beijing University of Chemical Technology. KX is grateful to the
National Natural Science Foundation of China (21602119 and
U1504208).
Conflicts of interest
a
b
Isolated yields. 2a (0.3 mmol), 2,3-dimethylindole (0.5
mmol), substituted aryne (0.2 mmol), KF/18-C-6 (0.7 mmol),
There are no conflicts to declare.
c
THF (2 mL) for 24 h at 0 ˚C.
spectroscopic analysis.
Determined by NMR
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