Acylalkylation of Arynes Generated from o-Iodoaryl Triflates with Hydrosilanes and Cesium Fluoride

Article abstract of DOI:10.1021/acs.orglett.1c00279

An efficient method to generate aryne intermediates from o-iodoaryl triflates triggered by triethylsilane and cesium fluoride is disclosed. This method realized the acylalkylation of arynes using easily available o-iodoaryl triflate-type precursors, which was difficult when using conventional nucleophilic activators. A wide range of (hetero)arenes including various fused benzothiazoles were successfully synthesized from o-iodoaryl triflates by virtue of their good accessibility and divergent transformations of aryne intermediates.

Full text of DOI:10.1021/acs.orglett.1c00279

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Letter
Acylalkylation of Arynes Generated from o‑Iodoaryl Triflates with
Hydrosilanes and Cesium Fluoride
Mai Minoshima, Keisuke Uchida, Yu Nakamura, Takamitsu Hosoya, and Suguru Yoshida*
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ABSTRACT: An efficient method to generate aryne intermediates from o-iodoaryl
triflates triggered by triethylsilane and cesium fluoride is disclosed. This method
realized the acylalkylation of arynes using easily available o-iodoaryl triflate-type
precursors, which was difficult when using conventional nucleophilic activators. A
wide range of (hetero)arenes including various fused benzothiazoles were successfully
synthesized from o-iodoaryl triflates by virtue of their good accessibility and divergent
transformations of aryne intermediates.
ryne chemistry realizing unique transformations has
attracted a broad range of chemists in synthetic organic
facilitated the aryne generation from o-iodophenyl triflate (1a),
enabling efficient acylalkylation with 1,3-diketone 2a (Table
1). No benzyne generation took place when using n-butylzinc
bromide (entry 1). Although benzyne precursor 1a was
consumed when using sodium borohydride as an activator, a
complex mixture of products was obtained, in which the
acylalkylated product 3a was not detected (entry 2). In sharp
contrast, the treatment of o-iodophenyl triflate (1a) with
triethylsilane and cesium fluoride in the presence of 1,3-
diketone 2a at room temperature furnished α-(2-
benzoylphenyl)acetophenone (3a) in moderate yield via the
benzyne generation and subsequent acylalkylation (entry 4),
whereas the sole use of triethylsilane resulted in the
quantitative recovery of benzyne precursor 1a (entry 3).
When using Lewis bases such as potassium fluoride and 18-
crown-6, tetrabutylammonium difluorotriphenylsilicate
(TBAT), or cesium carbonate instead of cesium fluoride for
the benzyne generation, the yields of acylalkylation product 3a
significantly decreased (entries 5−7). Triphenylsilane with
cesium fluoride also facilitated the benzyne generation (entry
8). In contrast, no aryne generation took place when using
Lewis acids instead of cesium fluoride (entries 9−11). Because
volatile triethylsilane easily rendered the purification of 3a, we
further optimized the reaction conditions using triethylsilane
and cesium fluoride (entries 12−15). As a result, performing
the reaction at a higher temperature resulted in efficient
benzyne generation (entries 12 and 13). We successfully
A
chemistry, pharmaceutical sciences, and materials chemis-
try.1−3 The recent remarkable progress of synthetic methods
through aryne intermediates generated from a range of
precursors such as o-silylaryl triflates and o-iodoaryl triflates
has significantly expanded the synthesizable arenes (Figure
1A). In particular, insertion reactions including the acylalky-
lation of arynes have allowed us to prepare various multi-
substituted arenes from o-silylaryl triflates (Figure 1B).4
Considering the good accessibility of o-iodoaryl triflates
owing to the well-studied iodination compared with silylation,
we herein developed a novel method for the efficient
acyclalkylation of aryne intermediates from o-iodoaryl triflates
(Figure 1C).
A wide variety of difunctionalizations of aryne intermediates
through insertion reactions have been achieved using o-silylaryl
triflates as aryne precursors with fluoride sources.1−3 In sharp
contrast, only a few insertion reactions using o-iodoaryl triflates
as aryne precursors have been reported so far because
nucleophilic activators such as n-butyllithium react with
arynophiles bearing electrophilic moieties. Over the course of
our synthetic aryne chemistry using various o-iodoaryl
triflates,5 we attempted the acylalkylation of benzyne with
1,3-diketone 2a by the treatment of o-iodophenyl triflate (1a)
with n-butyllithium, i-propylmagnesium chloride, or
(trimethylsilyl)methylmagnesium chloride (Figure 1D). As a
result, these attempts resulted in failure and affording complex
mixtures of side products. With the idea in mind that a variety
of nucleophilic reagents can activate the iodo group,6 we
envisioned that the acylalkylation of aryne intermediates could
be accomplished by the activation of o-iodoaryl triflates with a
suitable activator.
Received: January 25, 2021
Published: February 19, 2021
After an extensive screening of activators to generate aryne
intermediates, we found that triethylsilane with cesium fluoride
https://dx.doi.org/10.1021/acs.orglett.1c00279
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1868−1873
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Table 1. Optimization of the Reaction Conditions
a
entry
additive
temp.
yield (%)
1
2
3
4
n-BuZnBr (3.0 equiv)
NaBH4 (3.0 equiv)
Et3SiH (3.0 equiv)
Et3SiH (3.0 equiv)
CsF (3.0 equiv)
rt
rt
rt
rt
0
0
0
56
5
Et3SiH (3.0 equiv)
KF (3.0 equiv)
rt
29
18-crown-6 (3.0 equiv)
Et3SiH (3.0 equiv)
n-Bu4NPh3SiF2 (3.0 equiv)
Et3SiH (3.0 equiv)
Cs2CO3 (3.0 equiv)
Ph3SiH (3.0 equiv)
CsF (3.0 equiv)
Et3SiH (3.0 equiv)
BF3·OEt2 (3.0 equiv)
Et3SiH (3.0 equiv)
B(C6F5)3 (3.0 equiv)
Et3SiH (3.0 equiv)
AlCl3 (3.0 equiv)
Et3SiH (3.0 equiv)
CsF (3.0 equiv)
6
rt
0
2
7
rt
8
rt
67
0
9
rt
10
11
12
13
rt
0
rt
0
Figure 1. Transformations of aryne intermediates. (A) Trans-
formations of aryne intermediates generated from o-silyl and o-
iodoaryl triflates. (B) Acylalkylation of arynes using o-silylaryl triflates
as aryne precursors. (C) This work. (D) Initial attempts.
40 °C
70 °C
70 °C
70 °C
62
85
97
98
Et3SiH (3.0 equiv)
CsF (3.0 equiv)
Et3SiH (4.6 equiv)
CsF (4.6 equiv)
prepared acyalkylation product 3a in excellent yield by
increasing the amounts of o-iodophenyl triflate (1a),
triethylsilane, and cesium fluoride (entry 14). This acyclalky-
lation using o-iodophenyl triflate (1a) on a 1 mmol scale
proceeded uneventfully, showing good scalability (entry 15).
A wide variety of 1,3-dicarbonyl compounds 2 participated
in the acylalkylation of aryne intermediates using o-iodophenyl
triflate (1a) (Figure 2). Acylalkylation products 3b−3d were
synthesized under benzyne generation conditions from 1a with
triethylsilane and cesium fluoride without damaging methoxy,
chloro, and bromo groups. Benzyne generation and subsequent
acylalkylation with heterocyclic 1,3-di(2-thienyl)-1,3-propane-
dione (2e) also took place smoothly to provide diketone 3e in
high yield. Esters 3f−3h were efficiently prepared from 1a and
β-ketoesters, leaving the ester, methoxy, and fluoride moieties
untouched. Diethyl malonate was also applicable to the
acylalkylation using 1a, triethylsilane, and cesium fluoride,
providing diester 3i in moderate yield.
Acylalkylation products 3j−3q were successfully prepared
from a broad range of o-iodoaryl triflate-type aryne precursors
1 (Figure 3A). For instance, the generation of 3-methoxy- and
3-(benzyloxy)benzyne and the following acylalkylation pro-
ceeded efficiently to furnish 3j and 3k selectively in high yields.
We accomplished the synthesis of diketone 3l having a
terminal alkyne moiety in good yield through 3-
(propargyloxy)benzyne.5a The acylalkylation of 3-fluoroben-
zyne also proceeded to afford 3m in moderate yield, in which
the regioisomer was not observed.5i Diketones 3n−3p were
synthesized in good to excellent yields via 4,5-dimethox-
ybenzyne, 2,3-naphthalyne, and cyclopentene-fused benzyne
b
14
b c
,
15
Et3SiH (4.6 equiv)
CsF (4.6 equiv)
a
b
c
Isolated yields. 1.5 equiv of 1a was used. Experiment performed on
1.0 mmol scale.
from the corresponding o-iodoaryl triflate-type aryne pre-
cursors with triethylsilane and cesium fluoride. It is worth
noting that a benzothiazole-type aryne successfully participated
in the acylalkylation to provide diketone 3q in moderate
yield.5f These results clearly showed a clear benefit of this
method, which significantly improved the accessibility of
acylalkylation products by virtue of the good availability of o-
iodoaryl triflate-type precursors for generating functionalized
arynes such as 3-(propargyloxy)benzyne and thiazole-fused
benzyne.
The good accessibility of o-iodoaryl triflate-type aryne
precursors 1 would serve in the synthesis of functionalized
(hetero)arenes through the acylalkylation of aryne intermedi-
ates. Indeed, we achieved the synthesis of a variety of fused
benzothiazoles 4−6 from acylalkylated product 3q (Figure
3B). Isoquinolinothiazole 4 was synthesized from 3q by
treatment with ammonium acetate in hot acetic acid.7
Benzothiazole 3q also reacted with hydrazine hydrate,
furnishing diazepine-fused benzothiazole 5 in good yield.8
Furthermore, we accomplished the preparation of naphtho-
thiazole 6 by an iron-catalyzed reaction with phenylacetylene.9
These results clearly demonstrated that the acylalkylation of
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Figure 2. Acylalkylation of benzyne using various 1,3-dicarbonyl
compounds 2. See the Supporting Information for the structures of 2.
aThe reaction was performed using an aryne precursor (3.0 equiv),
Et3SiH (11 equiv), and CsF (11 equiv).
arynes generated from easily preparable o-iodoaryl triflates and
the following transformations expanded the synthesizable
(hetero)arenes.
To obtain insights into the reaction mechanism of the aryne
generation from o-iodoaryl triflates with triethylsilane and
cesium fluoride, we conducted control experiments (Figure 4).
Whereas 2-iodo-3-(triflyloxy)naphthalene (1g) was completely
consumed to generate 2,3-naphthalyne by treating with
triethylsilane and cesium fluoride in tetrahydrofuran (THF)
at 70 °C (Figure 4A), 2-iodonaphthalene (7) was quantita-
tively recovered under the conditions, and naphthalene (8)
was not detected (Figure 4B). This result apparently showed
that the significant electron-withdrawing triflyloxy group
promoted the C−I cleavage of o-iodoaryl triflates for the
aryne generation. Considering that the metalation of aryl
iodides can take place by a hydrosilane and Lewis base such as
lithium t-butoxide reported by Nakamura, Ilies, and cow-
orker,6c the generation of benzyne (II) through the C−I
activation and the liberation of the triflate anion would be
triggered by silicate I formed from triethylsilane and cesium
fluoride (Figure 4C). The resulting hydrogen iodide would
react with silicate I to generate hydrogen.
A broad range of arenes was prepared by the newly
developed aryne generation method from o-iodoaryl triflates
with triethylsilane and cesium fluoride (Figure 5). Indeed, [2 +
4] and [2 + 3] cycloaddition reactions with diene 9 and
nitrone 11 proceeded efficiently, similar to the case with a
silylmethyl Grignard reagent as an activator. Of note, we
realized the synthesis of arenes 14, 16, 18, and 20 by
transformations of aryne intermediates through insertion
reactions, which were previously reported using o-silylaryl
triflates as aryne precursors. For example, the acylalkylation of
benzyne using ethyl α-sulfonylacetate took place smoothly to
provide 14 without damaging the sulfone moiety.10 An
acridone synthesis was accomplished from o-iodophenyl triflate
(1a) and aniline 15 with triethylsilane and cesium fluoride.11
Figure 3. (A) Acylalkylation of arynes using various o-iodoaryl
triflates 1. (B) Synthesis of fused benzothiazoles 4−6 from 3q. See the
Supporting Information for details. aThe reaction was performed
using an aryne precursor (3.6 equiv), diketone 2a (1.0 equiv), Et3SiH
(11 equiv), and CsF (11 equiv).
The treatment of 1a and enamide 17 with triethylsilane and
cesium fluoride afforded isoquionoline 18 in moderate yield.12
Furthermore, we achieved the preparation of o-sulfanylaniline
20 by the thioamination of benzyne with sulfilimine 19.13
Because attempts at these transformations for the synthesis of
arenes 14, 16, 18, and 20 from o-iodophenyl triflate (1a)
resulted in failure when using (trimethylsilyl)-
methylmagnesium chloride as an activator, the aryne
generation method from o-iodoaryl triflates with triethylsilane
and cesium fluoride obviously enables us to synthesize
multisubstituted arenes by diverse aryne reactions owing to
the good accessibility of the aryne precursors.
The advantages of the aryne generation method from o-
iodoaryl triflates with triethylsilane and cesium fluoride were
successfully demonstrated by heteroaromatic ring formations
of a thiazolobenzyne intermediate (Figure 5). For example, the
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marin 23 showed blue fluorescence.16 Because it is not easy to
synthesize the corresponding o-silylaryl triflate-type thiazolo-
benzyne precursor, these results clearly show that the newly
developed aryne generation method from o-iodoaryl triflate-
type precursors significantly expanded the accessible benzo-
thiazoles. A wide range of novel (hetero)aromatic compounds
will be prepared by diverse difunctionalizations of various
(hetero)arynes owing to the mild aryne generation conditions
using easily available o-iodoaryl triflates.
In conclusion, we have developed an aryne generation
method from o-iodoaryl triflates with triethylsilane and cesium
fluoride, enabling diverse insertion reactions including the
acylalkylation of aryne intermediates. Because o-iodoaryl
triflate-type aryne precursors can be easily synthesized from
the corresponding phenols, the newly developed aryne
generation method will contribute to the synthesis of diverse
multisubstituted (hetero)arenes. Further studies including the
investigation of the detailed reaction mechanism and
applications to prepare bioactive aromatic compounds are
currently underway.
Figure 4. Mechanistic studies. (A) Consumption of 1g by
naphthalyne generation. (B) Attempt of the reduction of 7. (C)
Plausible reaction mechanism of the generation of benzyne (II) from
1a.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00279.
Experimental procedures and characterization of new
compounds including NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Suguru Yoshida − Laboratory of Chemical Bioscience,
Institute of Biomaterials and Bioengineering, Tokyo Medical
and Dental University (TMDU), Tokyo 101-0062, Japan;
orcid.org/0000-0001-5888-9330; Email: s-yoshida.cb@
tmd.ac.jp
Authors
Mai Minoshima − Laboratory of Chemical Bioscience,
Institute of Biomaterials and Bioengineering, Tokyo Medical
and Dental University (TMDU), Tokyo 101-0062, Japan
Keisuke Uchida − Laboratory of Chemical Bioscience,
Institute of Biomaterials and Bioengineering, Tokyo Medical
and Dental University (TMDU), Tokyo 101-0062, Japan
Yu Nakamura − Laboratory of Chemical Bioscience, Institute
of Biomaterials and Bioengineering, Tokyo Medical and
Dental University (TMDU), Tokyo 101-0062, Japan
Takamitsu Hosoya − Laboratory of Chemical Bioscience,
Institute of Biomaterials and Bioengineering, Tokyo Medical
and Dental University (TMDU), Tokyo 101-0062, Japan;
orcid.org/0000-0002-7270-351X
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00279
Figure 5. Various transformations of o-iodoaryl triflates. The yields
when using (trimethylsilyl)methylmagnesium chloride are shown in
brackets. See the Supporting Information for details. (A) Trans-
formations of 1a. (B) Transformations of 1i.
Notes
The authors declare no competing financial interest.
synthesis of thiazoloacridine 22 was achieved from o-iodoaryl
triflate 1i and o-benzoylaniline (21) through a thiazolobenzyne
intermediate.14 We also succeeded in the three-component
assembly of the thiazolobenzyne, diethyl malonate (2j), and
N,N-dimethylformamide (DMF), furnishing thiazolocoumarin
23 in moderate yield.15 Thiazoloacridine 22 and thiazolocou-
ACKNOWLEDGMENTS
■
We thank Dr. Yuki Sakata at Tokyo Medical and Dental
University for HRMS analyses. This work was supported by
JSPS KAKENHI grant numbers JP19K05451 (C; S.Y.) and
JP18H02104 (B; T.H.), the Naito Foundation (S.Y.), the
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Japan Agency for Medical Research and Development
(AMED) under grant number JP20am0101098 (Platform
Project for Supporting Drug Discovery and Life Science
Research, BINDS), and the Cooperative Research Project of
Research Center for Biomedical Engineering.
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