Rh(I)-Catalyzed Carbene Migration/Carbonylation/Cyclization: Straightforward Construction of Fully Substituted Aryne Precursors

Article abstract of DOI:10.1021/jacs.0c13012

The Rh(I)-catalyzed cascade formation of carbenoid followed by a carbonylative cyclization of silyl diynes has been established to achieve diverse ortho silyl-substituted phenolics, enabling access to fully substituted aryne precursors via a one-step fluorosulfurylation. The silyl mask on the termini of alkynes is demonstrated not only to suppress the undesired oxidation but also to control the selectivity of CO insertion. Straightforward access to fully substituted arynes was comprehensively established and applied for the efficient construction of polycyclic aromatic molecules.

Full text of DOI:10.1021/jacs.0c13012

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Communication
Rh(I)-Catalyzed Carbene Migration/Carbonylation/Cyclization:
Straightforward Construction of Fully Substituted Aryne Precursors
Guohao Zhu, Wen-Chao Gao, and Xuefeng Jiang*
Cite This: J. Am. Chem. Soc. 2021, 143, 1334−1340
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ABSTRACT: The Rh(I)-catalyzed cascade formation of carbenoid followed by a carbonylative cyclization of silyl diynes has been
established to achieve diverse ortho silyl-substituted phenolics, enabling access to fully substituted aryne precursors via a one-step
fluorosulfurylation. The silyl mask on the termini of alkynes is demonstrated not only to suppress the undesired oxidation but also to
control the selectivity of CO insertion. Straightforward access to fully substituted arynes was comprehensively established and
applied for the efficient construction of polycyclic aromatic molecules.
Scheme 1. Strategy for Fully Substituted Arynes Synthesis
rynes have long been recognized as powerful building
blocks for the construction of functional arenes due to
A
their excellent reactivity.1 Since Robert’s pioneer work on the
validation of the triple-bonded nature of benzyne in 1953, a
wide variety of arynes, such as naphthynes, pyridynes, and
indolynes have been reported and applied for the synthesis of
functional material molecules and natural products.2 Triphe-
nylenes, hexabenzotriphenylenes, and rubrenes, bearing a fully
substituted aromatic ring skeleton, were efficiently constructed
from benzyne, 9,10-phenanthryne, and naphthyne, respec-
tively.3 Meanwhile, arynes were efficiently employed for the
synthesis of polycyclic natural products. Ellipticine was
obtained through a cycloaddition reaction of pyridyne, and
the fully substituted aromatic system of dictyodendrin A was
constructed from a cascade reaction of benzyne (Scheme 1A).4
Regarding aryne generation, early methods relied on the
dehydrohalogenation of aryl halides under basic conditions.5
Subsequently, Kobayashi and co-workers developed a facile
method for the generation of arynes via the fluoride-induced
1,2-elimination of 2-(trimethylsilyl)aryl triflates,6 which were
accessed from ortho-halogenated phenols followed by the
introduction of a silyl substituent and leaving group (Scheme
1B).7 Recently, an innovative strategy for polycyclic aryne
syntheses was developed by Hoye’s group through a
hexadehydro-Diels−Alder (HDDA) process of triynes.8
On the basis of our research in the transition-metal-catalyzed
carbonylative cyclization reaction of aryne,9 we envisioned that
fully substituted aryne precursors could be afforded from yne-
ynamides via a cascade process of carbene migration, CO
insertion, and 6π electrocyclization (Scheme 1C). Never-
theless, the competition of oxidation between two types of
carbene and the sequential insertion of CO challenges the
straightforward concept.10,11 Because of the steric effect and
the hyperconjugative effect of a silicon substituent,12 a silyl
mask is designed for the yne-ynamide to suppress undesired
oxidation and the selectivity of CO insertion, facilitating aryne
precursors simultaneously. Herein, we disclose a cascade
strategy involving the carbonylative cyclization of silyl diynes
via Rh(I)-catalyzed carbene migration and CO insertion
Received: December 16, 2020
Published: January 13, 2021
https://dx.doi.org/10.1021/jacs.0c13012
J. Am. Chem. Soc. 2021, 143, 1334−1340
© 2021 American Chemical Society
1334

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Communication
d
a
Table 1. Effects of Silyl Substituents and N-O Oxides
Table 2. Substrate Scope
a
Reaction conditions: substrates 1 (0.1 mmol), [Rh(COD)Cl]2 (5
mol %), 2-bromopyridine-N-oxide (0.2 mmol), tetrahydrofuran (2.0
b
a
mL), CO balloon, 60 °C. Reaction conditions: 1a (0.1 mmol),
Reaction conditions: substrates (0.1 mmol), Rh(COD)Cl2 (5 mol
[Rh(COD)Cl]2 (5 mol %), N-O oxides (0.2 mmol), tetrahydrofuran
%), N−O-4 compounds (0.13 mmol), tetrahydrofuran (2.0 mL), CO
c
b
(2.0 mL), CO balloon, 60 °C. 10% of a 1,3-silyl migration product
balloon, 60 °C, isolated yields. Tetrahydrofuran/dichloroethane =
d
was detected. 1H NMR yields are based on substrates 1 with 1,1,1,2-
1:1, 80 °C.
tetrachloroethane as the internal standard. TMS: trimethylsilyl; TES:
triethylsilyl; TBS: t-butyldimethylsilyl; TIPS: triisopropylsilyl;
TBDPS: t-butyldiphenylsilyl.
was substantially influenced by the size of the silicon
substituent.
Furthermore, diverse N-O oxides were tested for the O-
transfer step. When pyridine-N-oxide (N−O-1) was applied as
a nucleophile, the desired product P1 was obtained in only 9%
yield combined with 35% of diketone byproduct SP-1 and 26%
of starting material, in which pyridine formed after a
transformation deactivated the rhodium catalyst. Diverse 2-
substituted N-O oxides were screened; considering that the
steric hindrance effect on the 2-position of pyridine-N-oxide
may inhibit the attack on the metal carbene center Int I,14 2-
methyl substituted N-O oxide (N−O-2) was less effective for
this reaction, while the σ-withdrawing group 2-chloro and
bromo-substituted N-O oxide (N−O-3 and N−O-4) increased
the yields of P1 to 68% and 76%, respectively. Notably, 2-
bromopyridine-N-oxide achieved a higher efficiency than the 3-
substituted isomer (N−O-5). These results suggest that both
steric and electronic effects on the 2-position of pyridine-N-
oxide played an important role in preventing the oxidized
byproduct SP-1. A larger steric hindrance, such as that of 2,6-
dichloropyridine-N-oxide (N−O-6), resulted in a rather low
reaction efficiency with 84% of the starting material recovered.
Delightedly, the yield of P1 could be further improved to 82%
by decreasing the equivalent of N−O-4 (for more details see
the Supporting Information).
assisted via a silyl mask effect to construct fully substituted
aryne precursors, which are further applied for conjugated
polycyclic aromatic molecule construction.
To realize the assumption, yne-tethered ynamide 1 and N-
oxides were conducted in the presence of [Rh(COD)Cl]2
catalyst under CO atmosphere.13 First, the effect of
substituents on a terminal alkyne was investigated. As shown
in Table 1, when R is Ph, the desired cyclization product P1
was obtained in only 6% yield, together with overoxidative
diketone byproducts SP-1 (11% yield) and SP-2 (57% yield).
Considering that the adjustable silyl groups will provide a steric
hindrance to suppress the attack from N-oxide to rhodium
carbenoid Int II, silyl-terminated diynes were examined as
substrates. The trimethylsilyl (TMS) group successfully
inhibited the oxidized byproduct SP-2, affording the
cyclization product P1 in 12% yield. Altering from TMS to
TES group, the yield of P1 increased to 36%. To our delight,
the TBS-terminated diyne was the best choice and furnished
P1 in 76% yield. However, further increasing the steric effect of
silyl substituents (TIPS and TBDPS) is inclined to result in the
oxidized byproduct SP-1 (26% and 64%, respectively). These
results demonstrated that the transfer rate of Rh(I) carbene
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a b d
, ,
Table 3. Generation of Arynes for the Construction of Polycyclic Aromatic Molecules
a
b
Fluorosulfurylation conditions: phenolics (0.4 mmol), fluorosulfuryl imidazolium salt (1.2 equiv), Et3N (1.5 equiv), MeCN (2.0 mL), rt. Diels−
c
Alder conditions: diene (0.05 mmol), 3a (3.0 equiv), CsF (3.0 equiv), MeCN (1.0 mL), rt. KF instead of CsF, and the reaction was conducted at
100 °C. Isolated yields.
d
With the optimized conditions in hand, the scope of the
Rh(I)-catalyzed carbene migratory carbonylative cyclization
process was explored. All yne-ynamide substrates could be
readily prepared via a Cu-catalyzed amidation of alkynyl
bromides.15 As shown in Table 2, the reaction of yne-ynamides
with different N-sulfonyl groups was first investigated, leading
to the desired phenolics in 76−83% yields (2a−2c).
Meanwhile, a gram-scale operation was performed, successfully
affording 2a in 83% yield (1.06 g, 2.5 mmol). Next, substrates
with both electron-donating and electron-withdrawing sub-
stituents on aromatic rings were subjected to this trans-
formation, delivering the corresponding products in excellent
yields (2d−2i). Various functional groups such as ester (2j),
amide (2k), and acetyl (2l) were well-tolerated to produce the
corresponding phenolics in 68−89% yields. In addition, yne-
ynamides bearing 3,4-disubstituted aromatic rings afforded the
desired 2m−2o in 67−77% yields under standard conditions,
and the 1,3-silyl migration byproduct was detected in these
cases in 10−31% yields.16 Furthermore, this reaction could be
extended to heterocycle-substituted diynes, remarkably leading
to the corresponding products 2p and 2q in 82% and 73%
yields. The structure of pyrrolocarbazole lactam, which
frequently existed in carbazole alkaloids serving as a potent
PARP-1 inhibitor,17 was successfully assembled via this
method (2r and 2s). In particular, naturally occurring motifs
such as amino acids, menthol, and estrone are compatible with
this system affording the corresponding phenolic derivatives in
moderate to good yields (2t−2v). The structures of 2a and 2r
were further confirmed by X-ray diffraction.18
Polycyclic aromatic molecules (PAMs) have attracted
considerable attention due to their unique optoelectronic
properties in materials science.19 Among the various synthetic
methods of producing PAMs, arynes as a powerful tool played
an indispensable role. In particular, a cycloaddition reaction of
arynes allowed the incorporation of benzene rings through
multiple bond formation in one step, thus providing a
significant increase in the structural complexity.20 After the
library of ortho TBS-substituted phenolics was established,
diverse fully substituted aryne precursors were readily available
through one-step fluorosulfurylation21 and then employed to
generate arynes for the construction of polycyclic aromatic
molecules. As shown in Table 3, the cycloaddition reaction of
aryne precursor 3a with various dienes including furan, 1,3-
diphenylisobenzofuran, and tetracyclone were conducted
smoothly by adding F− sources in acetonitrile, leading to the
corresponding polycyclic aromatic products in 78−92% yields
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molecule enabled the further possibility of derivation via cross-
coupling. Meanwhile, the thiophene-substituted aryne could be
well-generated in this way obtaining the cycloaddition product
in 69% yield (4g). To our delight, these polycyclic aromatic
molecules exhibited a strong fluorescence in solution,
displaying the potential application in organic photoelectric
materials.22
Scheme 2. Control Experiments
To gain further insight into the carbonylative cyclization
process, a mechanistic study was conducted. First, besides the
TBS substituent, other substituents were also accommodated
on the alkyne termini. For example, substrates bearing methyl
and phenyl groups led to the oxidized byproduct SP-2 in 28%
and 57% yields, respectively. An increase of steric hindrance (R
= tBu) could prevent the byproduct SP-2, but it was
unfavorable for CO insertion. These experiments demon-
strated that not only steric hindrance but also an electronic
effect of a silicon substituent on alkyne termini played a crucial
role in the cascade process (Scheme 2a). Next, in order to trap
the possible ketene intermediate during the transformation,
para CF3-substituted substrate 1i was subjected to the standard
conditions in the presence of 10 equiv of methanol;23 the
envisaged methyl ester 5i was obtained in 38% yield together
with the desilylated counterpart 6i (26%) and a trace amount
of desired product 2i, further confirming our hypothesis.
Additionally, the treatment of ynamide 7a under standard
conditions only led to diketone product 8a in 61% yield, which
demonstrated Rh carbenoid in the first step is not suitable for
CO insertion (Scheme 2b).
Scheme 3. Possible Mechanism
According to the observations above, a plausible mechanism
is proposed (Scheme 3). First, a catalytic Rh(I) species was
preferentially bounded to an electron-richer triple bond,
followed by the attack from N-oxide to furnish α-oxo Rh(I)
carbenoid B.10c Fortunately, the oxidized byproduct B′ was
fully inhibited by both a steric and electronic effect between
substrate and pyridine N-oxide. Next, the migration of
rhodium carbene B from a benzyl position to an α-position
of a silyl group afforded intermediate C.24,25 Then, the silyl
vinylketene E was generated from intermediate D via CO
coordination and insertion followed by the dissociation and
regeneration of Rh.26 The mask effect of silyl provided a steric
hindrance to exclude the attack from 2-bromopyridine N-oxide
to rhodium carbene again, successfully preventing the second
oxidation risk from C to diketone C′. Meanwhile, a
hyperconjugative σ−π donation from Si−C bond to in-plane
carbonyl π-orbital27 perfectly stabilized the ketene intermedi-
ate for the process of CO insertion. Subsequently, a 6π-
electrocyclization of E afforded the intermediate F followed by
a 1,5-H shift to obtain cyclohexadienone G.16c The following
aromatization possesses two possible pathways: the desired
product H was afforded via a 1,3-H migration in dynamics
dominant (path A), while the byproduct I was generated via a
1,3-Si migration at a higher temperature determined by
thermodynamic stability (path B).16,28
In summary, we have developed a Rh(I)-catalyzed carbene
migration/carbonylation/cyclization cascade reaction for the
facile construction of fully substituted arynes, which display a
great potential for organic photoelectric material synthesis.
The steric and hyperconjugative effect of the silyl substituent
on the alkyne is crucial in this cascade process to control the
selective CO insertion by preventing the oxidation of the
carbenoid intermediate. Further studies on construction of
diverse arynes with structurally high complexity for an organic
(4a−4c). The structure of 4b was further confirmed through
X-ray analysis.18 Additionally, diverse fully substituted aryne
precursors were subjected to the cycloaddition reaction with
1,3-diphenylisobenzofuran. Both electron-rich and electron-
deficient functional groups on the aromatic rings were well-
tolerated and furnished the corresponding products in 85−
92% yields (4d−4f), in which a para-bromide-substituted
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light-emitting diode (OLED) via this strategy are ongoing in
our lab.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c13012.
■
sı
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Experimental procedures; NMR spectral, X-ray, and
analytical data for all new compounds (PDF)
Crystallographic data (CIF)
Crystallographic data (CIF)
Crystallographic data (CIF)
AUTHOR INFORMATION
Corresponding Author
■
Xuefeng Jiang − Shanghai Key Laboratory of Green Chemistry
and Chemical Process, School of Chemistry and Molecular
Engineering, East China Normal University, Shanghai
200062, P. R. China; State Key Laboratory of
Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032,
P. R. China; orcid.org/0000-0002-1849-6572;
Email: xfjiang@chem.ecnu.edu.cn
́ ́
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Authors
Guohao Zhu − Shanghai Key Laboratory of Green Chemistry
and Chemical Process, School of Chemistry and Molecular
Engineering, East China Normal University, Shanghai
200062, P. R. China
Wen-Chao Gao − Shanghai Key Laboratory of Green
Chemistry and Chemical Process, School of Chemistry and
Molecular Engineering, East China Normal University,
Shanghai 200062, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c13012
Notes
The authors declare no competing financial interest.
(6) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Fluoride-induced 1,2-
Elimination of O-trimethylsilylphenyl Triflate to Benzyne Under Mild
Conditions. Chem. Lett. 1983, 12, 1211−1214.
ACKNOWLEDGMENTS
■
The authors are grateful for the financial support provided by
NSFC (21971065, 21722202, and 21672069), STCSM
(20XD1421500, 20JC1416800, and 18JC1415600), Innovative
Research Team of High-Level Local Universities in Shanghai
(SSMU-ZLCX20180501), and Professor of Special Appoint-
ment (Eastern Scholar) at Shanghai Institutions of Higher
Learning.
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Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
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