KHMDS mediated synthesis of 9-arylfluorenes from dibenzothiophene dioxides and arylacetonitriles by tandem SNAr-decyanation-based arylation

Article abstract of DOI:10.1039/c8ob02355g

A straightforward KHMDS mediated synthetic route to 9-arylfluorenes from readily available starting materials has been developed. This reaction involves S_NAr reactions of dioxide with arylacetonitriles, followed by decyanation reaction. The pro

Full text of DOI:10.1039/c8ob02355g

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KHMDS mediated synthesis of 9-arylfluorenes
from dibenzothiophene dioxides and
arylacetonitriles by tandem SNAr-decyanation-
based arylation†
Cite this: Org. Biomol. Chem., 2018,
16, 7815
Received 21st September 2018,
Accepted 15th October 2018
DOI: 10.1039/c8ob02355g
Saketh Mylavarapu,‡ Mamta Yadav‡ and M. Bhanuchandra
*
rsc.li/obc
A straightforward KHMDS mediated synthetic route to 9-arylfluor- ducts would adversely affect the performance of the device in
enes from readily available starting materials has been developed. which they are used. Moreover, the commercial non-avail-
This reaction involves SNAr reactions of dioxide with arylacetoni- ability of the catalysts and limited reaction scope hinder the
triles, followed by decyanation reaction. The proposed transform- practical utility of the aforementioned methods.
ation can also be used to furnish a densely arylated indene.
On the other hand, there are very few reports on the tran-
sition-metal-free synthesis of 9-arylfluorene derivatives. In one
such example, i.e., the reduction of 9-aryl-9-fluorenol with an
Et3SiH/Et2O·BF3 system, the precursor carbinol was prepared
by the reaction of 9-fluorenone with aryllithium or an aryl
9-Arylfluorenes are important structural frameworks that find
application in diverse fields.1 More specifically, because of
their unique electronic and photonic properties,2 these com-
pounds are widely used in materials science,3 i.e., in organic
electronics,4 blue fluorescent organic light-emitting materials,5
semiconductors,6 photovoltaic cells,7 etc. The C–H bond at the
9-position of 9-arylfluorenes is acidic and hence can serve as a
ligand in organometallic chemistry.8 Much research has been
undertaken to prepare 9-arylfluorene derivatives in the last few
years. Pre-functionalized 9-bromofluorene was found to react
with phenylboronic acid in the presence of organostannoxane-
supported palladium nanoparticles as the catalyst to afford the
corresponding 9-arylfluorenes.9 Hao and co-workers reported a
zinc-mediated coupling of 9-bromofluorene with arenes to
obtain 9-arylfluorenes.10 An alternative and straightforward
method in this regard is the palladium-catalyzed direct C–H
bond arylation of fluorene with aryl halides.11 A combination
of bimetallic Pd–Sn and AgPF6 is reported to catalyze the intra-
molecular tandem reaction of 2-arylbenzaldehyde with elec-
tron-rich arenes to give the desired 9-arylfluorenes.12 However,
most of the reported methods require transition-metal cata-
lysts or specially designed precursors that are obtained via
multiple synthetic steps. Furthermore, these strategies are
efficient, but the residual transition metals in the final pro-
Grignard reagent via a two-pot approach (method-I, Fig. 1).13
A
Lewis acid or Brønsted acid could be used to catalyze the intra-
molecular Friedel–Crafts cyclization of an ortho-biaryl alcohol/
acetate (method-II).14
In general, substituted biaryls provide regio-isomeric mix-
tures in Friedel–Crafts cyclization.14a In 2014, Zhang and
Zheng et al. developed a TfOH-catalyzed tandem ring-closing
Department of Chemistry, School of Chemical Sciences and Pharmacy,
Central University of Rajasthan, Bandarsindri, Rajasthan-305 817, India.
E-mail: mallibhanuchandra@curaj.ac.in
†Electronic supplementary information (ESI) available: Experimental procedure,
spectra. CCDC 1866811. For ESI and crystallographic data in CIF or other elec-
tronic format see DOI: 10.1039/c8ob02355g
Fig. 1 Recent strategies for transition-metal-free synthesis of
9-arylfluorenes.
‡These authors contributed equally.
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reaction of 2-arylbenzaldehydes with electron-rich arenes (SiMe3)2 (potassium hexamethyldisilazide; KHMDS, 3 equiv.)
(method-III).15 Ping Liu and Yan Liu groups jointly developed at 80 °C in dioxane for 16 h. After careful analysis of the NMR
an efficient method based on the reductive coupling of spectra, we concluded that the abovementioned product was
N-tosylhydrazones with arylboronic acids, a two-step reaction 9-phenylfluorene (3a). Compound 3a was probably formed by
in which the reactants were added sequentially (method-IV).16 the SNAr reactions of 2a with 1a, followed by a decyanation
In spite of these elegant methods, there still remain need to reaction. This result prompted us to identify the optimal reac-
develop novel strategies to synthesize 9-arylfluorene under tion conditions for the formation of 3a. When using 2 equiv.
transition-metal free conditions. Recently, Yorimitsu’s group of the starting material 2a, the reaction did not proceed to
reported a very interesting reaction, the aromatic metamorpho- completion even at 80 °C. Hence, we decided to perform the
sis of dibenzothiophenes into a different ring system. This optimization studies using 3 equiv. of 2a at 100 °C for 24 h in
method is valuable as it allows for the cleavage of aromatic various solvents. The yield of the product 3a was 69% using
rings, which are typically considered uncleavable.17 In particu- dioxane as a solvent (entry 2). Other nonpolar solvents such as
lar, the twofold SNAr reaction of dibenzothiophene dioxide is toluene yielded poor amount of 3a (entry 3). The reaction with
considered a sustainable strategy for aromatic metamorphosis, other ethereal solvents such as THF and 1,2-dimethoxyethane
since it does not require transition-metal catalysts. (DME) gave the desired product 3a in moderate yield (entries 4
Dibenzothiophene dioxide can be transformed into dibenzo- and 5). Highly polar DMSO did not found to be good solvent
phosphole oxide,18 spirocyclic 9,9-diarylfluorenes,19 and carba- (entry 6). Use of nonpolar solvent petroleum ether gave the
zoles20 by reaction with phenylphosphine, cyclic diaryl- corresponding product in 81% yield (entry 7). Finally, the
methanes, and aniline nucleophiles, respectively. The key to effect of bases was examined (entries 8–13). Other alkaline
the success of this twofold SNAr reaction is the choice of a suit- metal salts of hexamethyl disilazane such as Li(NSiMe3)2 (1.0
able nucleophile, such as a species with reasonably acidic M in toluene) and Na(NSiMe3)2 was inferior (entries 8 and 9).
geminal protons. With these concepts in mind, we envisioned The reaction with Cs2CO3 K2CO3, and K3PO4 resulted with no
that benzyl cyanide21 would be a promising coupling partner conversion (entries 10–12). The strong base KOH was not
for dibenzothiophene dioxide in twofold SNAr reactions to effective (entry 13).22 These results suggest that 3 equiv. of 2a,
access 9-phenyl-9H-fluorene-9-carbonitrile (7).
3 equiv. of K(NSiMe3)2 base in toluene/pet.ether at 100 °C for
We commenced our study using reaction conditions similar 24 h would be a better reaction condition for SNAr-decyanation
to those established for carbazole synthesis (Table 1, entry based arylation process. With the optimized reaction condition
1).20 To our delight, we could isolate a highly nonpolar in hand, we next involved in exploring the scope of the
product by the treatment of dibenzo[b,d]thiophene 5,5-dioxide reaction.
(1a) with benzylcyanide (2a; 2 equiv.) in the presence of KN
At first, reaction between 1a and various arylacetonitrile 2
were investigated under the optimized reaction condition
(Table 2).
Table 1 Optimization of reaction conditiona
The electron neutral phenyl substituted acetonitrile 2a
reacted with 1a to give the corresponding product 3a in 81%
yield. 9-([1,1′-Biphenyl]-4-yl)-9H-fluorene (3b) was isolated in
albeit in moderate yield. Electron donating substituents such
as methyl and methoxy on para-position of phenyl ring furn-
ished the corresponding products 3c and 3d in 93% and 52%
yields, respectively. Notably, typical hydroxyl protecting groups
such as methoxymethyl and benzyl moieties in 3e and 3f sur-
vived under the basic reaction conditions. The N-heterocycle
pyrazole bearing arylacetonitrile 2g was tolerated under the
reaction condition to give 3g in 62% yield. The presence of
α-acidic protons on pyrazole ring might be responsible for
obtaining moderate yield. Synthetically viable halo groups sur-
vived under the reaction condition. The reaction of 2-(4-chloro-
phenyl)acetonitrile (2h) and 2-(4-fluorophenyl)acetonitrile (2i)
with 1a were conducted independently and the corresponding
products 3h and 3i were isolated in 78% and 57% yields,
respectively. The meta-substituted 9-(m-tolyl)-9H-fluorene (3j)
was obtained in excellent yield. Despite its steric hindrance, 2-
(2-methoxyphenyl)acetonitrile (2k) participated in the reaction
to give 3k in reasonable yield.
Entry
Baseb
Solvent
Yieldc (%)
1
2
3
4
5
6
7
8
KN(SiMe3)2
KN(SiMe3)2
KN(SiMe3)2
KN(SiMe3)2
KN(SiMe3)2
KN(SiMe3)2
KN(SiMe3)2
LiN(SiMe3)2
NaN(SiMe3)2
Cs2CO3
1,4-Dioxane
1,4-Dioxane
Toluene
THF
DME
21d
69
71
38
67
13
81
66
DMSO
Petroleum ether
Petroleum ether
Petroleum ether
Petroleum ether
Petroleum ether
Petroleum ether
Petroleum ether
9
35
10
11
12
13
NRe
NR
NR
10
K2CO3
K3PO4
KOH
a Reactions were carried out using 1a (0.5 mmol), 2a (1.5 mmol), base
(1.5 mmol), solvent (1 mL) at 100 °C for 24 h. b KN(SiMe3)2 and LiN
Next, we examined the scope of dibenzothiophene dioxide,
and the results are shown in Table 3. In general, Friedel–Crafts
cyclization reactions may deliver mixture of regio-isomeric pro-
(SiMe3)2 were 0.5 and 1.0
M solutions in toluene, respectively.
c Isolated yield. d Performed with 2a (1.0 mmol) at 80 °C for 16 h. e NR:
No reaction.
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Table 2 Substrate scope of aryl acetonitrilesa,b
Table 3 Substrate scope of dibenzothiophene dioxidea,b
a Reactions were carried out using 1a (0.5 mmol). b Isolated yields.
Scheme 1 Synthesis of 1,2,3-triphenyl-1H-indene.
densely arylated 1,2,3-triphenyl-1H-indene (6) was obtained from
simple starting materials, albeit in moderate yield (Scheme 1).
To identify the mechanism underlying the SNAr-decyana-
tion based arylation, the following experiments were con-
ducted (Scheme 2).
We initially envisioned that the transformation proceeds via
a two-fold SNAr reaction to give 7, which then undergoes reduc-
tive decyanation in the presence of K(NSiMe3)2.23 After per-
forming a few control experiments, we were able to isolate 7 by
reducing the amounts of the base and 2a, in a shorter time.
The structure of 7 was unambiguously confirmed by X-ray
analysis (see ESI†). Subsequent exposure of 7 to K(NSiMe3)2 at
100 °C for 12 h did not afford 3a, and the starting material was
a Reactions were carried out using 1a (0.5 mmol). b Isolated yields.
ducts (method-II and III, Fig. 1). It is worthy to note that the
transformations with substituted dibenzothiophene dioxides
are immanent regio-specific. For instance, the initial substi-
tution pattern on dibenzothiophene dioxides were retained in
the final products 4b–e. π-Extended 9-arylfluorenes such as
3,9-diphenyl-9H-fluorene (4b) and 3,6,9-triphenyl-9H-fluorene
(4c) were isolated in 69% and 76% yields, respectively.
Similarly, 2-pyrazolyl substituted sulfone 1d smoothly under-
went reaction with 2a to furnish 4d as a sole product in albeit
moderate yield. Other regio-isomeric sulfone such as 3-phenyl-
dibenzothiophene 5,5-dioxide (1e) participated in the reaction
to give 4e in 53% yield.
Encouraged by the good performance of the SNAr-decyana-
tion-based arylation strategy, we next investigated the effect of
2,3-diphenylbenzothiophene 1,1-dioxide (5). Eventually, the Scheme 2 Elucidation of mechanism.
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Scheme 3 Deuterium scrambling experiment.
partially decomposed. The mechanism for departure of
cyanide from 7 is unclear.24 The plausible mechanism for this
transformation would be an intermolecular SNAr reaction of
arylcyanide 2 with 1a in the presence of K(NSiMe3)2 provides
the corresponding ring opening product. Trimethylsilylation
of SO2K unit with HN-(SiMe3)2, generated in situ, delivers
8.20,25 Deprotonation of active methyne proton in compound 8
followed by intramolecular SNAr reaction would take place to
afford 7. The elimination of cyanide group from 7 would
provide 9-arylfluorene 3.
The acidic nature of the hydrogen at the 9-position of 3a
was confirmed by a deuterium scrambling experiment, which
revealed the formation of a stable Hückel aromatic compound
9-arylfluorenyl anion26 in the presence of KN(SiMe3)2
(Scheme 3).
In summary, we have demonstrated a KHMDS mediated
synthesis of 9-arylfluorenes from readily available starting
materials arylacetonitrile and dibenzothiophene dioxide.
The initial substitution pattern of the dibenzothiophene
derivatives was retained in the final 9-arylfluorenes. This
method could also be extended to the preparation of the
densely arylated 1,2,3-triphenyl-1H-indene. Current efforts are
directed at investigating the mechanism and application of the
final products in materials chemistry.
Conflicts of interest
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There are no conflicts to declare.
Acknowledgements
We gratefully acknowledge the DST-SERB (Grant Ref. No., ECR/
2016/001092 & EEQ/2017/000768); UGC (File No. 30-356/2017
(BSR) for research funding. We thank DST-FIST (Grant No., SR/
FST/CSI-257/2014(C) research grant to the Department of
Chemistry, and also thank Central University of Rajasthan for
support. S. M. and M. Y. thank DST and CSIR, respectively, for
fellowships. We are grateful to Dr Nagarjuna Kommu (UoH)
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