Catalytic c-c cleavage/alkyne-carbonyl metathesis sequence of cyclobutanones

Article abstract of DOI:10.1021/acs.orglett.0c01317

A ring-opening/alkyne-carbonyl metathesis sequence of alkyne-tethered cyclobutanones catalyzed by AgSbF₆ is realized for the first time to furnish multisubstituted naphthyl ketones under mild conditions. A range of substrates decorated with various substituents at different positions were all well accommodated. Preliminary mechanistic studies show that silver salt acted as a Lewis acid to facilitate both C-C cleavage of the cyclobutanone moiety and the subsequent metathesis between C═O and CC bonds.

Full text of DOI:10.1021/acs.orglett.0c01317

pubs.acs.org/OrgLett
Letter
Catalytic C−C Cleavage/Alkyne−Carbonyl Metathesis Sequence of
Cyclobutanones
Jiqiang Gao,# Chunhui Liu,# Zhongjuan Li, Haotian Liang, Yuhui Ao, Jinbo Zhao, Yuchao Wang,*
Yuanqi Wu, and Yu Liu*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c01317
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A ring-opening/alkyne−carbonyl metathesis se-
quence of alkyne-tethered cyclobutanones catalyzed by AgSbF6 is
realized for the first time to furnish multisubstituted naphthyl
ketones under mild conditions. A range of substrates decorated
with various substituents at different positions were all well
accommodated. Preliminary mechanistic studies show that silver
salt acted as a Lewis acid to facilitate both C−C cleavage of the
cyclobutanone moiety and the subsequent metathesis between CO and CC bonds.
ctivation of carbon−carbon bonds by transition-metal
expansion of cyclobutanones with unsaturated motifs to extend
the reactivity space. Herein we disclose the first Ag-catalyzed
ring-opening-metathesis sequence of alkyne-tethered cyclo-
butanones, wherein both the C−C and CO bonds of the
cyclobutanone moiety were cleaved synergistically (path d).
We envisioned that proper metal salts would function as
Lewis acid catalysts to facilitate the selective C−C bond
cleavage of cyclobutanones leading to the conjugated enone
intermediate. Introduction of a pendant alkyne would provide
an opportunity for a further intramolecular alkyne−carbonyl
metathesis sequence using the same catalyst (Scheme 2, top).
Although Lewis acids such as TiCl4, EtAlCl2, and BF3·Et2O,
A
catalysts has shown unique potentials in molecule
reorganization, providing intriguing transformations and
synthetic strategies that are otherwise difficult to achieve by
traditional methods.1 The release of ring strain in small rings
provides an extra driving force for such a purpose, making
them versatile substrates in a range of molecule reorganiza-
tions.2 In particular, catalytic ring expansion of cyclobutanones
with unsaturated motifs such as carbonyl groups, alkenes,
allenes, and alkynes provides efficient access to various cyclic
scaffolds.3 In general, these processes can be classified into the
following patterns (Scheme 1): (a) oxidative addition of
Scheme 1. Catalytic Ring-Expansion Reactions of
Cyclobutanones with Unsaturated Chemical Motifs
Scheme 2. Proposed Catalytic Ring-Opening/Metathesis
Sequence of Alkyne-Tethered Cyclobutanones
transition metals with cyclobutanones leading to five-
membered cyclic acylmetal species,4a−c followed by migratory
insertion with pendant unsaturated moiety (path a);4d−k (b) β-
carbon elimination of cyclobutanolates generated by either
oxidative cyclization of the two moieties with metals (path b)5
or addition of in situ generated metallic moiety with the
carbonyl of cyclobutanones (path c).6 Apart from the above
advances, other catalytic ring-expansion processes have rarely
been disclosed. Based on our interest in ring-opening reactions
of small rings,7 we engaged in developing unprecedented ring
Received: April 16, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01317
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
among others, typically in stoichiometric amounts, have been
reported to promote ring-opening of 3-donor-substituted
cyclobutanones (the “push−pull” structure),8 such a catalytic
ring-opening/alkyne−carbonyl metathesis (ROACM) se-
quence has never been realized before.9 Notably, alkyne−
carbonyl metathesis (ACM) has emerged as an efficient
pathway to α,β-unsaturated compounds.10 Compared to
aldehydes, however, the low reactivity of ketones makes
them reluctant to undergo such a transformation with simple
alkynes.11 It is especially challenging for simple conjugated
enones, which are normally the final products of ACM
reactions, to be applied for further metathesis sequence
(Scheme 2, bottom).12 Herein we present our success in this
field, which employs cyclobutanones as synthons of conjugated
enones for the ACM reaction, delivering naphthyl ketones as
final products, a frequently present scaffold in fine chemicals,
pharmaceuticals, agrochemicals, among others.13
reaction temperature resulted in slight erosion of the yield
(entry 13), while lower temperatures had a deleterious effect
(entries 14 and 15). Finally, the catalyst loading could be
reduced to 10 mol %, delivering 2a in comparative yield (entry
16).
With the optimized conditions in hand, we turned to explore
the generality of our protocol (Scheme 3). As shown, besides
a
Scheme 3. Generality on the Aromatic Moieties
We initiated our study by evaluating the ROACM reaction
of the model substrate 1a with AgSbF6 as catalyst (Table 1).
a
Table 1. Optimization of Reaction Conditions
b
entry
Lewis acid
solvent
DMF
1,4-dioxane
THF
CH2Cl2
CHCl3
CCl4
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgOTf
AgNO3
Sc(OTf)3
Zn(OTf)2
Fe(acac)3
AgSbF6
AgSbF6
AgSbF6
AgSbF6
60
60
60
60
60
60
60
60
60
60
60
60
70
50
40
60
5
5
0
64
82
50
70
23
0
11
0
0
79
77
72
80
DCE
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
9
10
11
12
13
14
15
c
16
a
Reactions were performed with 1a (0.2 mmol), Lewis acid (20 mol
b
c
%), solvent (2 mL), 12 h. Determined by crude 1H NMR. 10 mol %
of AgSbF6 was added.
a
All reactions were performed on a 0.3 mmol scale, with isolated
yields.
Solvents were found to exert a profound influence on the
reactivity. Thus, the product 2a was obtained in 5% yield in
DMF or 1,4-dioxane, but not detected in THF (entries 1−3).
Strikingly, the yield of 2a was significantly improved in
dichloromethane (entry 4). Other chlorinated solvents could
also be employed, with CHCl3 as the best candidate, providing
the target compound in 82% yield (entries 5−7). A screening
of the Lewis acid catalysts revealed that both the metal source
and counterion played a pivotal role. Specifically, markedly
inferior results were observed with AgOTf or AgNO3 as
catalysts (entries 8 and 9). The reaction was more sluggish
using Sc(OTf)2, leading to 2a in only 11% yield (entry 10). No
reaction took place in the presence of other metal salts such as
Zn(OTf)2 and Fe(acac)3 (entries 11 and 12). Elevating the
the model substrates, which provided the naphthyl ketone 2a
in 77% isolated yield, cyclobutanone derivatives decorated with
pendant alkynes that possess a diverse set of aromatic groups
could be well tolerated. Substrates bearing o-, m-, or p-tolyl
substituents all worked smoothly under the standard
conditions, offering products 2b−2d in high yields, suggesting
the insensitivity of the system to steric effect. Electron-
donating methoxy substituent was also accommodated, and the
naphthyl ketones were generated in moderate to good yields
(2e, 2f). An acceptable yield could still be achieved with a
2,4,5-trimethoxy substituted phenyl as alkyne terminus (2g).
Electron-withdrawing ester and nitro groups could be
B
https://dx.doi.org/10.1021/acs.orglett.0c01317
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
tolerated, albeit affording the products 2h and 2i in lower
yields. Fluoro- and chloro-containing products 2j and 2k were
obtained in high yields from the corresponding cyclobutanone
derivatives. The generality of the system was further showcased
by the tolerance of naphthyl and thiophene moiety, as products
2l and 2m were uneventfully afforded in comparable yields.
Variation of the arene core was next investigated. Various
substituents including methyl-, fluoro-, chloro-, and trifluor-
omethyl groups were all accommodated, and the final products
2n−2r were invariably prepared in ≥70% yields. The structure
of the methoxy product 2o was unambiguously determined by
X-ray diffraction study. Finally, starting from naphthyl
substrate, phenanthrenylphenyl methanone 2s was afforded
in moderate yield.
In conjugation with our mechanistic proposal, which
features a cation intermediate (Scheme 7, B), we postulated
that placing a proper substituent on the 3-position of
cyclobutanone moiety would be favorable as stabilization of
the cation fragment can enhance the reactivity. Indeed, the
substrates containing a methyl group reacted exceptionally
facilely, affording dialkylnaphthyl ketones 4a−4c in up to
quantitative yields (Scheme 4). The X-ray diffraction analysis
of 4a also confirmed its structure. Other alkyl substituents such
as ethyl, n-butyl, and phenethyl groups showed comparable
results, leading to the corresponding naphthyl ketones 4d−4h
in high yields. Replacing the alkyl group with a phenyl ring had
no deleterious effect on the reaction, providing target
compounds 4i−4k smoothly. To our delight, cyclobutanones
bearing mono- or gem-dimethyl substituents at the α-position
of the carbonyl group were compatible, with the more
hindered C−C bond being selectively cleaved (4l−4n). This
is especially notable, since cyclobutanones bearing extra
substituents at the α-position of the carbonyl group have
seldom been applied in transition-metal-catalyzed ring-
expansion systems.14 In a Rh-catalyzed intramolecular allene-
involved ring-expansion reaction of α-methyl cyclobutanones,
the C−C bond was cleaved selectively at the less bulky C4
position.14b
The reaction could be performed on a gram scale, delivering
the target compound 2a in excellent yield (Scheme 5). The
Scheme 5. Application of the Reaction System
a
Scheme 4. Generality on the Cyclobutanone Moieties
potential applicability of the system was further illustrated by
transformation of this naphthyl ketone product. Oxidation of
the methyl group was easily achieved by SeO2 to deliver 1-
benzoyl-2-naphthoic acid 5.15 Conversion to acyl chloride and
subsequent intramolecular Friedel−Crafts reaction resulted in
benz[a]anthracene-7,12-dione 6, which is the core structure of
angucycline antibiotics that exhibit a large spectrum of
biological properties including antibacterial, antiviral, and
cytostatic activities, among others.16
Additional studies were conducted to shed light on the
reaction mechanism (Scheme 6). When the alkyne moiety was
omitted from the substrate, diphenyl cyclobutanone 7 was
transformed to α, β-unsaturated ketone 8 in moderate yield
under the standard conditions (eq 1). To explore the
stereoselectivity of the ring-opening process, naphthyl cyclo-
butanone 9 was subjected to the conditions and conjugated
enone 10 was obtained as a single E-isomer (eq 2). The
appreciably lower yield compared with the diphenyl substrate 7
again demonstrates the enhancement of the reactivity by the
extra substituent at the 3-position. Moreover, when alkyne-
tethered enone (E)-11 was prepared and tested under the
standard conditions, naphthyl ketone 2a was obtained, albeit in
a significantly lower yield (eq 3).11,12 Residual water seems to
play an important role in the system, since the reaction was
appreciably retarded in the presence of molecular sieves (eq 4).
Consistently, when extra D2O was added into the reaction
system, methyl group was partly deuterated. Addition of 18O-
water did not lead to labeled product (eq 5). Finally, When
α,α-bisdeuterated substrate d2-3n was applied, monodeuter-
ated product d-4n was obtained exclusively (eq 6). As
comparison, trideuterated diaromatic ketone d3-2a was
a
All reactions were performed on a 0.3 mmol scale, with isolated
yields.
C
https://dx.doi.org/10.1021/acs.orglett.0c01317
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 6. Preliminary Mechanistic Studies
Figure 1. Computed energy profiles for the ring-opening process.
ring-opening indicate that the C−C bond cleavage process may
be involved as a rate-determining step.
Based on the above investigations and literature prece-
dents,8−12 a plausible reaction pathway is proposed in Scheme
7. The reaction proceeds by Lewis acid activation of the
Scheme 7. Proposed Mechanism
generated starting from d4-1a with full deuteration on the α-
positions (eq 7).
To gain a better understanding of the mechanistic details,
density functional theory (DFT) calculations were performed
on the Ag-promoted ring-opening process on b3lyp/g-
31G(d)/SDD(Ag) level of theory. As shown in Figure 1,
coordination between the substrate and AgSbF6 delivers
complex A1 or A2, depending on the poise of Ag coordinated
to cyclobutanone. C−C bond cleavage of A1 occurs through
TS1 with an activation barrier of 24.7 kcal/mol, leading to
cationic species B. Subsequent σ-bond rotation provides Int1
with a slight uphill. From this intermediate, an interesting
concerted protonation/deprotonation process takes place with
the aid of two molecules of H2O. This step requires a 5.5 kcal/
mol barrier, leading to a steep downhill to C with a large free
energy difference of 53.3 kcal/mol. In contrast, conversion of
A2 is accompanied by higher free energies for both the C−C
cleavage and generation of enone E. The energy profiles of the
cyclobutanone moiety to furnish cationic intermediate B,8
which provides Int1 via σ-bond rotation, leaving space for two
H2O molecules to participate in the concerted deprotonation/
protonation process to deliver enone C. Ag(I)-assisted
isomerizatioin17 and subsequent [2 + 2] cycloaddition would
give oxacyclobutene F, which undergoes retro-[2 + 2]
cycloaddition11,12 to produce the final product and releases
the silver catalyst.
In conclusion, we have developed a novel intramolecular
alkyne participated ring-expansion reaction of cyclobutanone
derivatives. Silver salt was utilized as catalyst for the first time
to facilitate the ring-opening metathesis sequence, in which
both C−C and CO bonds are cleaved and reorganized,
leading to multisubstituted naphthyl ketones under mild
conditions. The study paves an unprecedented pathway for
transition-metal-catalyzed structural reorganization of cyclo-
D
https://dx.doi.org/10.1021/acs.orglett.0c01317
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
butanones, leaving space for more types of inter- and
intramolecular transformations. Further studies regarding the
detailed mechanism and extension of the reaction patterns are
in progress.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01317
Author Contributions
#J.G. and C.L. contributed equally.
ASSOCIATED CONTENT
* Supporting Information
■
Notes
sı
The authors declare no competing financial interest.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01317.
ACKNOWLEDGMENTS
■
Experimental procedures and characterization data for
all new compounds (PDF)
Financial support from the National Natural Science
Foundation of China (Nos. 21602015, 21703195), Jilin
Provincial “13th Five Year Plan” Science and Technology
Project (No. JJKH20181022KJ) and Talent Development
Fund of Jilin Province are gratefully acknowledged.
Accession Codes
CCDC 1967107 and 1967473 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
REFERENCES
■
(1) For selected reviews: (a) Jun, C.-H. Transition Metal-Catalyzed
Carbon−Carbon Bond Activation. Chem. Soc. Rev. 2004, 33, 610−
618. (b) Satoh, T.; Miura, M. Catalytic Processes Involving β-Carbon
Elimination. Top. Organomet. Chem. 2005, 14, 1−20. (c) Murakami,
M.; Matsuda, T. Metal-Catalysed Cleavage of Carbon−Carbon
Bonds. Chem. Commun. 2011, 47, 1100−1105. (d) Dermenci, A.;
Coe, J. W.; Dong, G. Direct Activation of Relatively Unstrained
Carbon−Carbon Bonds in Homogeneous Systems. Org. Chem. Front.
2014, 1, 567−581. (e) Souillart, L.; Parker, E.; Cramer, N.
Asymmetric Transformations via C−C Bond Cleavage. Top. Curr.
Chem. 2014, 346, 163−193. (f) C-C Bond Activation. In Topics in
Current Chemistry. Dong, G., Ed.; Springer-Verlag: Berlin, 2014; Vol.
346. (g) Souillart, L.; Cramer, N. Catalytic C−C Bond Activations via
Oxidative Addition to Transition Metals. Chem. Rev. 2015, 115,
9410−9464. (h) Kim, D.-S.; Park, W.-J.; Jun, C.-H. Metal−Organic
Cooperative Catalysis in C−H and C−C Bond Activation. Chem. Rev.
2017, 117, 8977−9015. (i) Chen, P.-H.; Billett, B. A.; Tsukamoto, T.;
Dong, G. “Cut and Sew” Transformations via Transition-Metal-
Catalyzed Carbon−Carbon Bond Activation. ACS Catal. 2017, 7,
1340−1360. (j) Song, F.; Gou, T.; Wang, B.-Q.; Shi, Z.-J. Catalytic
Activations of Unstrained C−C Bond Involving Organometallic
Intermediates. Chem. Soc. Rev. 2018, 47, 7078−7115. (k) Deng, L.;
Dong, G. Carbon-Carbon Bond Activation of Ketones. Trends Chem.
2020, 2, 183.
AUTHOR INFORMATION
Corresponding Authors
■
Yuchao Wang − Department of Chemistry, Jilin Provincial Key
Laboratory of Carbon Fiber Development and Application,
College of Chemistry and Life Science, Changchun University of
Technology, Changchun 130012, P.R. China;
Email: wangyc057@ccut.edu.cn
Yu Liu − Department of Chemistry, Jilin Provincial Key
Laboratory of Carbon Fiber Development and Application,
College of Chemistry and Life Science, Changchun University of
Technology, Changchun 130012, P.R. China; orcid.org/
0000-0003-1304-9498; Email: yuliu@ccut.edu.cn
Authors
Jiqiang Gao − Department of Chemistry, Jilin Provincial Key
Laboratory of Carbon Fiber Development and Application,
College of Chemistry and Life Science, Changchun University of
Technology, Changchun 130012, P.R. China
Chunhui Liu − School of Chemistry and Chemical Engineering,
Xuchang University, Xuchang, Henan 461000, P.R. China;
College of Chemistry, and Institute of Green Catalysis,
Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
Zhongjuan Li − Department of Chemistry, Jilin Provincial Key
Laboratory of Carbon Fiber Development and Application,
College of Chemistry and Life Science, Changchun University of
Technology, Changchun 130012, P.R. China
Haotian Liang − Department of Chemistry, Jilin Provincial Key
Laboratory of Carbon Fiber Development and Application,
College of Chemistry and Life Science, Changchun University of
Technology, Changchun 130012, P.R. China
Yuhui Ao − Department of Chemistry, Jilin Provincial Key
Laboratory of Carbon Fiber Development and Application,
College of Chemistry and Life Science, Changchun University of
Technology, Changchun 130012, P.R. China
Jinbo Zhao − Department of Chemistry, Jilin Provincial Key
Laboratory of Carbon Fiber Development and Application,
College of Chemistry and Life Science, Changchun University of
Technology, Changchun 130012, P.R. China
(2) For selected reviews, see: (a) Namyslo, J. C.; Kaufmann, D. E.
The Application of Cyclobutane Derivatives in Organic Synthesis.
Chem. Rev. 2003, 103, 1485−1538. (b) Rubin, M.; Rubina, M.;
Gevorgyan, V. Transition Metal Chemistry of Cyclopropenes and
Cyclopropanes. Chem. Rev. 2007, 107, 3117−3179. (c) Seiser, T.;
Saget, T.; Tran, D. N.; Cramer, N. Cyclobutanes in Catalysis. Angew.
Chem., Int. Ed. 2011, 50, 7740−7752. (d) Matsuo, J. 1,4-Zwitterionic
Intermediates Formed by Cleavage of a Cyclobutane Ring and Their
Cycloaddition Reactions. Tetrahedron Lett. 2014, 55, 2589−2595.
(e) Vemula, N.; Pagenkopf, B. L. Synthesis and Reactivity of Alkoxy-
Activated Cyclobutane-1,1-dicarboxylates. Org. Chem. Front. 2016, 3,
1205−1212. (f) Fumagalli, G.; Stanton, S.; Bower, J. F. Recent
Methodologies That Exploit C−C Single-Bond Cleavage of Strained
Ring Systems by Transition Metal Complexes. Chem. Rev. 2017, 117,
9404−9432.
(3) For a review, see: (a) Xu, T.; Dermenci, A.; Dong, G. Transition
Metal-Catalyzed C−C Bond Activation of Four-Membered Cyclic
Ketones. Top. Curr. Chem. 2014, 346, 233−257. For selected recent
reports: Kondo, T.; Taguchi, Y.; Kaneko, Y.; Niimi, M.; Mitsudo, T.
Ru-and Rh-Catalyzed C-C Bond Cleavage of Cyclobutenones:
Reconstructive and Selective Synthesis of 2-Pyranones, Cyclo-
pentenes, and Cyclohexenones. Angew. Chem., Int. Ed. 2004, 43,
5369−5372. (b) Matsuda, T.; Shigeno, M.; Murakami, M.
Asymmetric Synthesis of 3,4-Dihydrocoumarins by Rhodium-
Catalyzed Reaction of 3-(2-Hydroxyphenyl) cyclobutanones. J. Am.
Chem. Soc. 2007, 129, 12086−12087. (c) Li, B.-S.; Wang, Y.; Jin, Z.;
Yuanqi Wu − Department of Chemistry, Jilin Provincial Key
Laboratory of Carbon Fiber Development and Application,
College of Chemistry and Life Science, Changchun University of
Technology, Changchun 130012, P.R. China
E
https://dx.doi.org/10.1021/acs.orglett.0c01317
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Zheng, P.; Ganguly, R. Y.; Chi, Y. R. Carbon−Carbon Bond
Activation of Cyclobutenones Enabled by the Addition of Chiral
Organocatalyst to Ketone. Nat. Commun. 2015, 6, 6207−6211.
(d) Chen, P.; Sieber, J.; Senanayake, C. H.; Dong, G. Rh-Catalyzed
Reagent-Free Ring Expansion of Cyclobutenones and Benzocyclobu-
tenones. Chem. Sci. 2015, 6, 5440−5445. (e) Okumura, S.; Sun, F.;
Ishida, N.; Murakami, M. Palladium-Catalyzed Intermolecular
Exchange between C−C and C−Si σ-Bonds. J. Am. Chem. Soc.
2017, 139, 12414−12417. (f) Cuccu, F.; Serusi, L.; Luridiana, A.;
Secci, F.; Caboni, P.; Aitken, D. J.; Frongia, A. Tandem Wittig
Reaction−Ring Contraction of Cyclobutanes: A Route to Function-
alized Cyclopropanecarbaldehydes. Org. Lett. 2019, 21, 7755−7758.
(g) Turnu, F.; Luridiana, A.; Cocco, A.; Porcu, S.; Frongia, A.; Sarais,
G.; Secci, F. Catalytic Tandem Friedel−Crafts Alkylation/C4−C3
Ring-Contraction Reaction: An Efficient Route for the Synthesis of
Indolyl Cyclopropanecarbaldehydes and Ketones. Org. Lett. 2019, 21,
7329−7332.
4611. (b) Matsuda, T.; Shigeno, M.; Makino, M.; Murakami, M.
Enantioselective C−C Bond Cleavage Creating Chiral Quaternary
Carbon Centers. Org. Lett. 2006, 8, 3379−3381. (c) Cao, J.; Chen, L.;
Sun, F.-N.; Sun, Y.-L.; Jiang, K.-Z.; Yang, K.-F.; Xu, Z.; Xu, L.-W. Pd-
Catalyzed Enantioselective Ring Opening/Cross-Coupling and Cyclo-
propanation of Cyclobutanones. Angew. Chem., Int. Ed. 2019, 58,
897−901. (d) Sun, Y.-L.; Wang, X.-B.; Sun, F.-N.; Chen, Q.-Q.; Cao,
J.; Xu, Z.; Xu, L.-W. Enantioselective Cross-Exchange between C−I
and C−C σ Bonds. Angew. Chem., Int. Ed. 2019, 58, 6747−6751.
(e) Sun, F.-N.; Yang, W.-C.; Chen, X.-B.; Sun, Y.-L.; Cao, J.; Xu, Z.;
Xu, L.-W. Enantioselective Palladium/Copper-Catalyzed C−C σ-
Bond Activation Synergized with Sonogashira-type C(sp3)−C(sp)
Cross-Coupling Alkynylation. Chem. Sci. 2019, 10, 7579−7583.
(7) (a) Liu, Y.; Ma, S. Unique Reactivity of Grignard Reagents
towards Cyclopropenyl-Carboxylates-Highly Selective Carbon−Car-
bon Bond Cleavage. Chem. Sci. 2011, 2, 811−814. (b) Liu, Y.; Ma, S.
Benzofurans or Isochromenes via the Ring-Opening Cyclization of
Cyclopropene Derivatives with Organolithiums. Org. Lett. 2012, 14,
720−723.
(4) (a) Murakami, M.; Amii, H.; Ito, Y. Selective Activation of
Carbon−Carbon Bonds next to a Carbonyl Group. Nature 1994, 370,
540−541. (b) Murakami, M.; Amii, H.; Shigeto, K.; Ito, Y. Breaking
of the C−C Bond of Cyclobutanones by Rhodium(I) and Its
Extension to Catalytic Synthetic Reactions. J. Am. Chem. Soc. 1996,
118, 8285−8290. (c) Murakami, M.; Itahashi, T.; Ito, Y. Catalyzed
Intramolecular Olefin Insertion into a Carbon−Carbon Single Bond.
J. Am. Chem. Soc. 2002, 124, 13976−13977. (d) Xu, T.; Ko, H. M.;
Savage, N. A.; Dong, G. Highly Enantioselective Rh-Catalyzed
Carboacylation of Olefins: Efficient Syntheses of Chiral Poly-Fused
Rings. J. Am. Chem. Soc. 2012, 134, 20005−20008. (e) Ko, H. M.;
Dong, G. Cooperative Activation of Cyclobutanones and Olefins
Leads to Bridged Ring Systems by a Catalytic [4 + 2] Coupling. Nat.
Chem. 2014, 6, 739−744. (f) Souillart, L.; Cramer, N. Highly
Enantioselective Rhodium(I)-Catalyzed Carbonyl Carboacylations
Initiated by C-C Bond Activation. Angew. Chem., Int. Ed. 2014, 53,
9640−9644. (g) Souillart, L.; Parker, E.; Cramer, N. Highly
Enantioselective Rhodium(I)-Catalyzed Activation of Enantiotopic
Cyclobutanone C-C Bonds. Angew. Chem., Int. Ed. 2014, 53, 3001−
3005. (h) Deng, L.; Jin, L.; Dong, G. Fused-Ring Formation by an
Intramolecular “Cut-and-Sew” Reaction between Cyclobutanones and
Alkynes. Angew. Chem., Int. Ed. 2018, 57, 2702−2706. (i) Zhu, Z.; Li,
X.; Chen, S.; Chen, P.; Billett, B. A.; Huang, Z.; Dong, G. Cobalt-
Catalyzed Intramolecular Alkyne/Benzocyclobutenone Coupling: C−
C Bond Cleavage via a Tetrahedral Dicobalt Intermediate. ACS Catal.
2018, 8, 845−849. (j) Sun, T.; Zhang, Y.; Qiu, B.; Wang, Y.; Qin, Y.;
Dong, G.; Xu, T. Rhodium(I)-Catalyzed Carboacylation/Aromatiza-
tion Cascade Initiated by Regioselective C−C Activation of
Benzocyclobutenones. Angew. Chem., Int. Ed. 2018, 57, 2859−2863.
(k) Deng, L.; Fu, Y.; Lee, S. Y.; Wang, C.; Liu, P.; Dong, G. Kinetic
Resolution via Rh-Catalyzed C−C Activation of Cyclobutanones at
Room Temperature. J. Am. Chem. Soc. 2019, 141, 16260−16265.
(5) (a) Murakami, M.; Ashida, S.; Matsuda, T. Nickel-Catalyzed
Intermolecular Alkyne Insertion into Cyclobutanones. J. Am. Chem.
Soc. 2005, 127, 6932−6933. (b) Murakami, M.; Ashida, S.; Matsuda,
T. Eight-Membered Ring Construction by [4 + 2 + 2] Annulation
Involving β-Carbon Elimination. J. Am. Chem. Soc. 2006, 128, 2166−
2167. (c) Murakami, M.; Ashida, S. Nickel-Catalysed Intramolecular
Alkene Insertion into Cyclobutanones. Chem. Commun. 2006, 4599−
4601. (d) Liu, L.; Ishida, N.; Murakami, M. Atom- and Step-
Economical Pathway to Chiral Benzobicyclo[2.2.2]octenones through
Carbon−Carbon Bond Cleavage. Angew. Chem., Int. Ed. 2012, 51,
2485−2488. (e) Julia-Hernandez, F.; Ziadi, A.; Nishimura, A.; Martin,
R. Nickel-Catalyzed Chemo-, Regio- and Diastereoselective Bond
Formation through Proximal C-C Cleavage of Benzocyclobutenones.
Angew. Chem., Int. Ed. 2015, 54, 9537−9541. (f) Zhou, X.; Dong, G.
Nickel-Catalyzed Chemo- and Enantioselective Coupling between
Cyclobutanones and Allenes: Rapid Synthesis of [3.2.2] Bicycles.
Angew. Chem., Int. Ed. 2016, 55, 15091−15095.
(8) (a) Murakami, M.; Kadowaki, S.; Fujimoto, A.; Ishibashi, M.;
Matsuda, T. Acids Direct 2-Styrylcyclobutanone into Two Distinctly
Different Reaction Pathways. Org. Lett. 2005, 7, 2059−2061.
(b) Matsuo, J.; Sasaki, S.; Tanaka, H.; Ishibashi, H. Lewis Acid-
Catalyzed Intermolecular [4 + 2] Cycloaddition of 3-Alkoxycyclobu-
tanones to Aldehydes and Ketones. J. Am. Chem. Soc. 2008, 130,
11600−11601. (c) Matsuo, J.; Sasaki, S.; Hoshikawa, T.; Ishibashi, H.
Intramolecular Formal [4 + 2] Cycloaddition of 3-Ethoxycyclobuta-
nones and Alkenes. Chem. Commun. 2010, 46, 934−936. (d) Shan,
G.; Sun, X.; Xia, Q.; Rao, Y. A Facile Synthesis of Substituted 2-
Alkylquinolines through [3 + 3] Annulation between 3-Ethoxycyclo-
butanones and Aromatic Amines at Room Temperature. Org. Lett.
2011, 13, 5770−5773. (e) Cheng, Y.; Han, X.; Ouyang, H.; Rao, Y. A
New Practical Approach towards the Synthesis of Unsymmetric and
Symmetric 1,10-Phenanthroline Derivatives at Room Temperature.
Chem. Commun. 2012, 48, 2906−2908. (f) Kawano, M.; Kiuchi, T.;
Negishi, S.; Tanaka, H.; Hoshikawa, T.; Matsuo, J.; Ishibashi, H.
Regioselective Inter- and Intramolecular Formal [4 + 2] Cyclo-
addition of Cyclobutanones with Indoles and Total Synthesis of
( )-Aspidospermidine. Angew. Chem., Int. Ed. 2013, 52, 906−910.
(g) Kuzuguchi, T.; Yabuuchi, Y.; Yoshimura, T.; Matsuo, J. Synthesis
of Multisubstituted Phenols by Formal [4 + 2] Cycloaddition of
Nucleophilic Alkynes with 3-Ethoxycyclobutanones. Org. Biomol.
Chem. 2017, 15, 5268−5271. (h) Igarashi, E.; Sakamoto, K.;
Yoshimura, T.; Matsuo, J. Formal [4 + 2] Cycloaddition of 3-
Phenylcyclobutanones with Nitriles. Tetrahedron Lett. 2019, 60, 13−
15.
(9) (a) For BF3·Et2O-catalyzed metathesis of ynamides and
cyclobutanones with retention of the four-membered ring, see: Sun,
Y.-L.; Chen, L.; Cao, J.; Sun, F.-N.; Xu, Z.; Zheng, Z.-J.; Cui, Y.-M.;
Xu, L.-W. Lewis Acid-Catalyzed Yne-Carbonyl Metathesis of
Ynamides and Cyclobutanones: Facile Synthesis of Functionalized
Alkylidenecyclobutanes. Asian J. Org. Chem. 2018, 7, 374−377. (b)
For stoichiometric TiCl4-promoted [4 + 2] cycloaddition of
nucleophilic alkynes with 3-ethoxycyclobutanones, see ref 8g.
(10) (a) For recent reports: Sun, J.; Keller, V. A.; Meyer, S. T.;
Kozmin, S. A. Silver-Catalyzed Aldehyde Olefination Using
Siloxyalkynes. Adv. Synth. Catal. 2010, 352, 839−842. (b) Bera, K.;
Sarkar, S.; Biswas, S.; Maiti, S.; Jana, U. Iron-Catalyzed Synthesis of
Functionalized 2H-Chromenes via Intramolecular Alkyne-Carbonyl
Metathesis. J. Org. Chem. 2011, 76, 3539−3544. (c) Liu, L.; Xu, B.;
Hammond, G. B. Construction of Cyclic Enones via Gold-Catalyzed
Oxygen Transfer Reactions. Beilstein J. Org. Chem. 2011, 7, 606−614.
(d) Bera, K.; Jalal, S.; Sarkar, S.; Jana, U. FeCl3-Catalyzed Synthesis of
Functionally Diverse Dibenzo[b,f]oxepines and Benzo[b]oxepines via
Alkyne−Aldehyde Metathesis. Org. Biomol. Chem. 2014, 12, 57−61.
(e) Nayak, M.; Kim, I. Alkyne Carbonyl Metathesis as a Means to
Make 4-Acyl Chromenes: Syntheses of ( )-Deguelin and ( )-Mun-
duserone. J. Org. Chem. 2015, 80, 11460−11467. (f) Saito, A.;
Tateishi, K. Synthesis of Heterocycles via Alkyne-Carbonyl Metathesis
(6) (a) Matsuda, T.; Makino, M.; Murakami, M. Synthesis of Seven-
Membered-Ring Ketones by Arylative Ring Expansion of Alkyne-
Substituted Cyclobutanones. Angew. Chem., Int. Ed. 2005, 44, 4608−
F
https://dx.doi.org/10.1021/acs.orglett.0c01317
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
of Unactivated Alkynes. Heterocycles 2016, 92, 607−630. (g) Murai,
K.; Tateishi, K.; Saito, A. Barluenga’s Reagent with HBF4 as an
Efficient Catalyst for Alkyne-Carbonyl Metathesis of Unactivated
Alkynes. Org. Biomol. Chem. 2016, 14, 10352−10356.
Intramolecular Coupling between Cyclobutanones and Trisubstituted
Allenes via C−C Activation. J. Am. Chem. Soc. 2015, 137, 13715−
13721.
(15) Clar, E.; Stewart, D. G. Aromatic hydrocarbons. Part LIX. 1:2−
3:4-Dibenzpyrene. J. Chem. Soc. 1951, 0, 687−690.
(11) For recent reports on metathesis reactions between alkynes and
ketones, see: (a) Jin, T.; Yamamoto, Y. Gold-Catalyzed Intra-
molecular Carbocyclization of Alkynyl Ketones Leading to Highly
Substituted Cyclic Enones. Org. Lett. 2007, 9, 5259−5262. (b) Jin, T.;
Yamamoto, Y. Gold-Catalyzed Synthesis of Polycyclic Enones from
Carbon Tethered 1,3-Enynyl Carbonyls via Tandem Heteroenyne
Metathesis and Nazarov Reaction. Org. Lett. 2008, 10, 3137−3139.
(c) Jin, T.; Yang, F.; Liu, C.; Yamamoto, Y. TfOH-Catalyzed
Intramolecular Alkyne−Ketonemetathesis Leading to Highly Sub-
stituted Five-Membered Cyclic Enones. Chem. Commun. 2009, 3533−
3535. (d) Liu, P.; Xu, B.; Hammond, G. B. Construction of Cyclic
Enones via Gold-Catalyzed Oxygen Transfer Reactions. Beilstein J.
Org. Chem. 2011, 7, 606−614. (e) Bera, K.; Sarkar, S.; Jalal, S.; Jana,
U. Synthesis of Substituted Phenanthrene by Iron(III)-Catalyzed
Intramolecular Alkyne−Carbonyl Metathesis. J. Org. Chem. 2012, 77,
8780−8786. (f) Parpart, S.; Boldt, S.; Ehlers, P.; Langer, P. Synthesis
of Unsymmetrical Aza-Ullazines by Intramolecular Alkynyl-Carbonyl
Metathesis. Org. Lett. 2018, 20, 122−125.
(16) (a) Rohr, J.; Thiericke, R. Angucycline group antibiotics. Nat.
Prod. Rep. 1992, 9, 103−137. (b) Krohn, K.; Rohr, J. Angucyclines:
Total Syntheses, New Structures, and Biosynthetic Studies of an
Emerging New Class of Antibiotics. Top. Curr. Chem. 1997, 188,
127−195. (c) Johnson, M. M.; Ngwira, K. J.; Rousseau, A. L.;
Lemmerer, A.; Koning, C. B. Novel Methodology for the Synthesis of
the Benz[a]anthracene Skeleton of the Angucyclines Using a Suzuki-
Miyaura/Isomerization/Ring Closing Metathesis Strategy. Tetrahe-
dron 2018, 74, 12−18.
(17) (a) Manojveer, S.; Balamurugan, R. In Situ Formed Acetal-
Facilitated Synthesis of Substituted Indene Derivatives from o-
Alkenylbenzaldehydes. Org. Lett. 2015, 17, 3600−3603. (b) Dethe, D.
H.; Murhade, G. M.; Ghosh, S. FeCl3-Catalyzed Intramolecular
Michael Reaction of Styrenes for the Synthesis of Highly Substituted
Indenes. J. Org. Chem. 2015, 80, 8367−8376. (c) Manojveer, S.;
Balamurugan, R. A Cascade Approach to Naphthalene Derivatives
from o-Alkynylbenzaldehydes and Enolizable Ketones via in-situ-
Formed Acetals. Eur. J. Org. Chem. 2015, 2015, 4254−4260.
(12) For metathesis reactions between alkynes and some special α,β-
unsaturated carbonyls, see: (a) Liu, L.; Zhang, J. Selectivity Control in
Lewis Acid Catalyzed Regiodivergent Tandem Cationic Cyclization/
Ring Expansion Terminated by Pinacol Rearrangement. Angew.
Chem., Int. Ed. 2009, 48, 6093−6096. (b) Liu, L.; Wei, L.; Zhang,
J. A Facile Route to Polysubstituted Naphthalenes and Benzofluor-
enols via Scandium Triflate-and Triflic Acid-Catalyzed Benzannula-
tion of 2-(2-Alkynylarylidene)-1,3-Dicarbonyl Compounds. Adv.
Synth. Catal. 2010, 352, 1920−1924. (c) Manojveer, S.;
Balamurugan, R. Synthesis of Naphthalene Derivatives from ortho-
Alkynylacetophenone Derivatives via Tandem in Situ Incorporation of
Acetal and Intramolecular Heteroalkyne Metathesis/Annulation. Org.
Lett. 2014, 16, 1712−1715. (d) Jung, Y.; Kim, I. Deformylative
Intramolecular Hydroarylation: Synthesis of Benzo[e]pyrido[1,2-
a]indoles. Org. Lett. 2015, 17, 4600−4603. (e) Nayak, M.; Kim, I.
Construction of Benzo-fused Indolizines, Pyrrolo[1,2-a]quinolines via
Alkyne−Carbonyl Metathesis. Org. Biomol. Chem. 2015, 13, 9697−
9708. (f) Nayak, M.; Singh, D. K.; Kim, I. Regiospecific Synthesis of
5-and 6-Acylated Naphtho[1,2-b]benzofurans via Intramolecular
Alkyne Carbonyl Metathesis. Synthesis 2017, 49, 2063−2073.
(g) Paul, K.; Jalal, S.; Kundal, S.; Chakraborty, B.; Jana, U. Iron-
Catalyzed Intramolecular Alkyne−Carbonyl Metathesis: A New
Cyclization Strategy for the Synthesis of Benzocarbazole and
Azepino[1,2-a]indole Derivatives. Synthesis 2017, 49, 4205−4212.
(13) (a) Ward, R. S. Lignans, Neolignans, and Related Compounds.
Nat. Prod. Rep. 1993, 10, 1−28. (b) Tang, G.; Nikolovska-Coleska, Z.;
Qiu, S.; Yang, C.-Y.; Guo, J.; Wang, S. Acylpyrogallols as Inhibitors of
Antiapoptotic Bcl-2 Proteins. J. Med. Chem. 2008, 51, 717−720.
(c) Zhang, H.; Guo, Z.; Wu, N.; Xu, W.; Han, L.; Li, N.; Han, Y. Two
Novel Naphthalene Glucosides and an Anthraquinone Isolated from
Rumex dentatus and Their Antiproliferation Activities in Four Cell
Lines. Molecules 2012, 17, 843−850. (d) Arenas, P.; Pena, A.; Rios,
D.; Benites, J.; Muccioli, G. G.; Calderon, P. B.; Valderrama, J. A. Eco-
Friendly Synthesis and Antiproliferative Evaluation of Some Oxygen
Substituted Diaryl Ketones. Molecules 2013, 18, 9818−9832.
(e) Feng, S.; Wang, G.; Zhang, H.; Pang, J. Graft Octa-Sulfonated
Poly(arylene ether) for High Performance Proton Exchange
Membrane. J. Mater. Chem. A 2015, 3, 12698−12708. (f) Ru, C.;
Gu, Y.; Duan, Y.; Zhao, C.; Na, H. Enhancement in Proton
Conductivity and Methanol Resistance of Nafion Membrane Induced
by Blending Sulfonated Poly(arylene ether ketones) for Direct
Methanol Fuel Cells. J. Membr. Sci. 2019, 573, 439−447.
(14) (a) Murakami, M.; Itahashi, T.; Amii, H.; Takahashi, K.; Ito, Y.
New Domino Sequences Involving Successive Cleavage of Carbon−
Carbon and Carbon−Oxygen Bonds: Discrete Product Selection
Dictated by Catalyst Ligands. J. Am. Chem. Soc. 1998, 120, 9949−
9950. (b) Zhou, X.; Dong, G. 4 + 1] vs [4 + 2]: Catalytic
G
https://dx.doi.org/10.1021/acs.orglett.0c01317
Org. Lett. XXXX, XXX, XXX−XXX