Rhodium-Catalyzed Room Temperature C-C Activation of Cyclopropanol for One-Step Access to Diverse 1,6-Diketones

Article abstract of DOI:10.1021/acs.orglett.0c00967

A rhodium-catalyzed room temperature C-C activation of cyclopropanol has been demonstrated for the single-step synthesis of a range of electronically and sterically distinct 1,6-diketones. This reaction proceeds efficiently in shorter reaction time following a highly atom-economical pathway. To illustrate the synthetic potential of 1,6-diketones, aldol and macrocyclization reactions have been successfully demonstrated. Preliminary mechanistic studies revealed the involvement of nonradical pathways.

Full text of DOI:10.1021/acs.orglett.0c00967

pubs.acs.org/OrgLett
Letter
Rhodium-Catalyzed Room Temperature C−C Activation of
Cyclopropanol for One-Step Access to Diverse 1,6-Diketones
Bedadyuti Vedvyas Pati,† Asit Ghosh,† and P. C. Ravikumar*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c00967
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A rhodium-catalyzed room temperature C−C
activation of cyclopropanol has been demonstrated for the
single-step synthesis of a range of electronically and sterically
distinct 1,6-diketones. This reaction proceeds efficiently in shorter
reaction time following a highly atom-economical pathway. To
illustrate the synthetic potential of 1,6-diketones, aldol and
macrocyclization reactions have been successfully demonstrated.
Preliminary mechanistic studies revealed the involvement of
nonradical pathways.
ransition-metal-catalyzed C−H and C−C functionaliza-
late derived from β-carbon elimination (C−C activation) of
cyclopropanol is limited,14 possibly due to a facile β-hydride
elimination pathway.15
T
tions have gained much attention in recent years owing to
their potential applications in organic synthesis.1,2 Although
extensive studies have been carried out on C−H bond
activation, strategies involving C−C bond activation remain
limited. In order to resolve this issue, significant efforts have
been made over the years finding new ways to activate various
types of C−C bonds.2,3 The most prominent strategies are
oxidative addition,2d β-carbon elimination,3a,c and aromatiza-
tion driven processes.3d Usually, C−C bond activation is a
thermodynamically unfavorable process; in essence, it is the
reverse reaction of the reductive elimination step. However,
the intrinsic strain of small carbocyclic rings has been
successfully exploited for C−C bond activation,4 wherein the
release of strain compensates for overcoming the thermody-
namic barrier. Pioneering research groups such as the Jun,
Dong, Bower, Marek, Yu, and Loh groups have demonstrated
the application of this useful strategy for the synthesis of
various scaffolds.5 Recently, we have demonstrated C−C bond
activation of cyclopropenone using a palladium catalyst for the
synthesis of highly substituted maleimides.6 We also
recognized that cyclopropanols which are easily accessible
from the Kulinkovich protocol are a useful synthon for the
synthesis of valuable molecular architectures.7 The efficacy of
cyclopropanols as a source of metal homoenolate was first
recognized by Kuwajima in 1985.8 It is worth mentioning that
the reactivity of transition metal homoenolates and catalyzed
ring opening cross-coupling reactions have been widely
exploited in numerous chemical transformations.9−13
Ryu and co-workers documented rhodium-catalyzed isomer-
ization of siloxycyclopropanes to give enol- and allyl-silyl ethers
(Scheme 1a-(i)).14a In another report, the synthesis 1,6-
diketones was reported by Ryu and co-workers from
siloxycyclopropanes (Scheme 1a-(ii)).16 However, it involves
the use of stoichiometric metal reagents and masked
cyclopropanol to access 1,6-diketones. It is essential to note
that due to the limitation of possible β-hydride elimination,
and isomerization pathways, catalytic self-coupling of metal
homoenolates was challenging.
Acyclic long-chain diketones, especially 1,6-diketones, are a
favorable and prominent carbon synthon for the construction
of pharmaceutically relevant and biologically active five- and
six-membered carbo- and heterocyclic compounds.17 Com-
pounds bearing a 1,6-bis(3,4-dimethoxyphenyl)hexane-1,6-
dione scaffold and their corresponding aldol adducts are
reported to have an effective inhibition profile against cytosolic
isoform hCA (Scheme 2).17g The aldol adducts obtained from
1,6-diketones are also the key precursor for the total synthesis
of Daucane and Sphenolobane derivatives.17i Moreover,
functionalized 1,6-diketones can also be subjected to various
synthetic transformations. For example, aldol condensa-
tion,17d,f McMurry coupling,17h macro-cyclization,17h and
reductive cyclization and pinacol coupling17b,e furnish an
Received: March 16, 2020
In this regard, a significant contribution has been made with
aryl halides, benzyl halides, and alkynes using palladium.9
Other transition metals such as copper,10 ruthenium,11
cobalt,12 and nickel13 have been employed in different
coupling reactions and rearrangements via metal homoeno-
lates. Nevertheless, transformations using rhodium-homoeno-
https://dx.doi.org/10.1021/acs.orglett.0c00967
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
to our expectations, when we screened solvents such as DCE,
TFT, MeOH, and toluene, we obtained monoketone 3a in
90%, 63%, 60%, and 76% yield instead of diketone 2a (Table 1,
Scheme 1. Previous and Present Work
a
Table 1. Optimization of Reaction Conditions
solvent
entry (0.1 M)
yield of
yield of
b
b
catalyst
additive
2a (%)
3a (%)
1
2
3
4
5
6
7
8
DCE
TFT
MeOH
Toluene
HFIP
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
[Cp*RhCl2]2 AgOAc
[Cp*RhCl2]2 AgOAc
[Cp*RhCl2]2 AgOAc
[Cp*RhCl2]2 AgOAc
[Cp*RhCl2]2 AgOAc
[Cp*RhCl2]2 AgOAc
[Cp*RhCl2]2 AgNTf2
[Cp*RhCl2]2 AgOCOCF3
[Cp*RhCl2]2 AgOTf
[Cp*RhCl2]2 AgBF4
[Cp*RhCl2]2 Ag2CO3
[Cp*RhCl2]2 Cs2CO3
[Cp*RhCl2]2 Na2CO3
[Cp*RhCl2]2 KHCO3
[Cp*RhCl2]2 NaHCO3
0
0
0
90
63
60
76
72
54
82
51
24
12
12
65
60
24
80
27
0
25
30
9
12
15
30
39
10
26
6
9
10
11
12
13
14
15
16
Scheme 2. Importance of 1,6-Diketone
11
42
[Cp*RhCl2]2 Ag2CO3
(0.5 equiv)
17
18
19
20
21
TFE
TFE
TFE
TFE
TFE
[Cp*RhCl2]2 Ag2CO3
54
64
72
57
55
33
26
24
25
22
(1 equiv)
[Cp*RhCl2]2 Ag2CO3
(1.5 equiv)
[Cp*RhCl2]2 Ag2CO3
(2 equiv)
[Cp*RhCl2]2 Ag2CO3
(2.5 equiv)
[Cp*RhCl2]2 Ag2CO3
(3 equiv)
22
23
TFE
TFE
[Cp*RhCl2]2
−
−
14
0
32
12
Ag2CO3
(2 equiv)
a
Unless otherwise specified, all reactions were carried out using
array of cyclic compounds (Scheme 2). Although several
synthetic utilities have been achieved with 1,6-diketones, there
has been less emphasis on their synthesis. Several methods
established in the recent past include β-hydroxy hydro-
peroxides, oxone-promoted oxidative ring opening of cyclo-
hexanone, magnesium-mediated reductive homocoupling of
enones, and gold-catalyzed hydration of alkynes. However, the
majority of them virtually involved multiple steps as well as
multicomponent reactions, use of nonreadily obtainable
starting materials, synthetically harsh reaction conditions, and
most importantly less efficiency and selectivity.18 Hence, a
general and efficient methodology for the preparation of 1,6-
diketones is highly desirable.
Perceiving the significance of rhodium-catalyzed C−C
activation of cyclopropanol and the synthetic usefulness of
1,6-diketones, we envisaged that cyclopropanol-derived rho-
dium-homoenolate can serve as an active precursor for the
preparation of 1,6-diketones. Herein, we report a rhodium-
catalyzed room temperature C−C activation of readily
available cyclopropanols for one-step access to diverse 1,6-
diketones (Scheme 1b).
[Cp*RhCl2]2 (5 mol %), additive (30 mol %), 1a (0.2 mmol) in a
solvent (0.1 M) for 15 min. Yield by NMR with 1,3,5-
trimethoxybenzene as internal reference.
b
entries 1−4). Formation of monoketone 3a could be attributed
to a facile protodemetalation of in situ generated rhodium-
homoenolate. The protodemetalation step appears to be faster
than β-hydride elimination and the perceived homocoupling of
rhodium homoenolates. Interestingly we obtained a lower yield
of monoketone 3a in a protic solvent such as methanol as
compared to DCE, TFT, and toluene. Therefore, we decided
to screen a few other protic solvents such as HFIP and TFE.
Although in lower yield, we were delighted to observe diketone
2a (25% and 30%, respectively) product along with
monoketone 3a (72% and 54% respectively) (Table 1, entries
5 and 6). To improve the yield of diketone 2a, we screened
various silver salts such as AgNTf2, AgOTf, AgOCOCF3,
AgBF4, and Ag2CO3 (Table 1, entries 7−11). Interestingly in
most cases monoketone 3a was the major product. However,
in the case of AgBF4 and Ag2CO3 there is a reversal in trend
leading to a significant decrease in the formation of isomerized
ketone 3a that was observed (Table 1, entries 10 and 11).
Since Ag2CO3 afforded 2a in 39% yield, we examined the effect
1-Benzylcyclopropan-1-ol 1a (0.2 mmol) was used as the
model substrate in the presence of the [Cp*RhCl2]2 (5 mol %)
catalyst to obtain the corresponding 1,6-diketone 2a. Contrary
B
https://dx.doi.org/10.1021/acs.orglett.0c00967
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
a
Scheme 3. Scope of Benzyl- and Alkyl-Substituted Cyclopropanol for the Synthesis of 1,6-Diketones
a
All reactions were carried out with 1 equiv of cyclopropanol 1, 2 equiv of Ag2CO3, and 5 mol % of [Cp*RhCl2]2 in the presence trifluoroethanol
(0.1 M) at room temperature for 15 min. Isolated yields are mentioned.
of other carbonate additives such as Cs2CO3, Na2CO3,
KHCO3, and NaHCO3 (Table 1, entries 12−15). Surprisingly,
none of the carbonate bases were found to be effective. A
careful analysis of the above results revealed that Ag2CO3 and
trifluoroethanol facilitate the formation of the homocoupled
product. Intrigued by this fact we speculated that use of higher
equivalents of Ag2CO3 might help the reaction pathway
enhancing the product yield. To our delight, a substantial
increment in the yield of 2a was noticed on increasing the
equivalence of Ag2CO3 from 0.3 to 1.0 (Table 1, entries 11 and
16−17). For further improvement of the yield, we tested 1.5,
2.0, 2.5, and 3.0 equiv of Ag2CO3 (Table 1, entries 18−21).
Satisfactorily, a significant rise in yield was attained on
increasing the equivalents of Ag2CO3 up to 2.0 (Table 1,
entries 17−19). However, the yield of 2a diminished when
more than 2.0 equiv of Ag2CO3 was used (Table 1, entries 20−
21). To check the influence of the rhodium catalyst and
Ag2CO3, two control experiments were conducted. In the
absence of Ag2CO3, only 14% formation of 2a was observed,
while, without the rhodium catalyst, homocoupled product was
not obtained (Table 1, entries 22−23). Hence, the use of 2.0
equiv of Ag2CO3 along with 5 mol % of [Cp*RhCl2]2 in
trifluoroethanol gave the best yield of 2a (Table 1, entry 19).
To assess the robustness of this developed protocol an array
of electronically and structurally diverse cyclopropanols 1, 4
were subjected to the optimized reaction conditions (Scheme
3). Initially, the scope of different benzyl-substituted cyclo-
propanols 2a−2i were evaluated. Cyclopropanol bearing
electron-donating benzyl substituents worked efficiently
affording 63−87% yields of their respective 1,6-diketones
2a−2d. Likewise, cyclopropanols bearing electron-withdrawing
para-substituents also produced their respective 1,6-diketones
2e−2g in 64−79% yield. These results reveal that the reaction
is facile for both electronically rich as well as electronically
poor benzyl-substituted cyclopropanols. Moreover, the dis-
ubstituted benzyl cyclopropanols 1h and 1i worked well,
producing 1,6-diketones 2h and 2i in good yields. Other alkyl-
substituted cyclopropanols such as γ-phenyl- and α-phenoxy-
substituted 1,6-diketones 2j and 2k were obtained in moderate
to good yield from 1j and 1k. It is worth noting that sterically
hindered cyclopropanol 1l reacted smoothly to afford the
desired 1,6-diketone 2l. Interestingly, 1,6-diketones containing
linear-chain and alicyclic substituents 2m−2p can also be
prepared in good yields.
To illustrate the generality of this protocol, various aryl- and
heteroaryl-substituted cyclopropanols were subjected to the
standard reaction conditions (Scheme 4). Cyclopropanols
carrying both electronically rich and electronically poor aryl
substituents successfully gave their respective 1,6-diketones.
Aryl cyclopropanols with an electron-donating group (o-, m-, p-
) afforded 1,6-diketones 5a−5f in moderate to good yield.
Similarly, electron-deficient cyclopropanols bearing a chloro,
fluoro, and trifluoromethyl arene substituent also produced
their corresponding 1,6-diketones 5g−5i in good yield.
Delightfully, excellent compatibility was observed with furan-
and thiophene-containing cyclopropanols resulting in their
analogous 1,6-diketones 5j and 5k.
Further, a 1.0 mmol scale reaction was carried out with 4a to
give 5a in 66% yield (Scheme 5a). Again, the potential of 1,6-
diketone as a synthetic precursor for different carbo- and
heterocyclic scaffolds was examined.17g,19 The aryl substituted
1,6-diketone 5e gave corresponding aldol adduct 6e in good
C
https://dx.doi.org/10.1021/acs.orglett.0c00967
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
reactions in the presence of radical scavengers such as
2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) and 2,6-di-
tert-butyl-4-methyl-phenol (BHT) showed no effect revealing a
nonradical pathway (Scheme 5d). To gain further insight into
the mechanism, we performed the deuterium incorporation
experiment under the standard reaction conditions using
deuterium-labeled cyclopropanol 1a-[d] (35% deuterated) in
the presence of d3-trifluoroethanol. No deuteration was
observed at the C-4 and C-5 positions of the diketone 2a-
[d], which again rules out the possibility of a radical pathway
(Scheme 5e).
Scheme 4. Scope of Aryl- and Heteroaryl-Substituted
Cyclopropanol for the Synthesis of 1,6-Diketones
a
Based on the above findings and literature precedents,9a,20
a
plausible catalytic cycle is shown (Scheme 6). Initially,
Scheme 6. Proposed Catalytic Cycle
a
All reactions were carried out with 1 equiv of cyclopropanol 4, 2
equiv of Ag2CO3, and 5 mol % of [Cp*RhCl2]2 in the presence of
trifluoroethanol (0.1 M) at room temperature for 15 min. Isolated
yields are mentioned.
Scheme 5. 1 mmol Scale Reaction, Synthetic Applications,
and Mechanistic Studies
[Cp*RhCl2]2 reacts with Ag2CO3 to form active rhodium
species I. Cyclopropanol 1 undergoes ligand exchange with I to
give alkoxide species II which can proceed in two different
pathways to reach species V. In pathway a, the alkoxide species
II follows β-carbon elimination to afford alkyl-rhodium
homoenolate III. Ligand exchange of III with another
molecule of cyclopropanol leads to the formation of species
IV that further undergoes β-carbon elimination to produce
dialkyl-rhodium species V. Alternatively, II can involve ligand
exchange with the second molecule of cyclopropanol prior to
β-carbon elimination to reach species V via the formation
species III′. It is noteworthy that a β-hydride elimination
pathway was not observed from homoenolate III or from
species V to give the corresponding β-hydride eliminated
product 3′. Finally, species V undergoes reductive elimination
to furnish product 2 along with rhodium(I)-species VI. Species
VI undergoes oxidation by Ag(I) to regenerate rhodium(III)-
species I. Formation of thin film of silver deposits on the sides
of the reaction vessel further confirms this fact.
In conclusion, we have developed an efficient rhodium-
catalyzed C−C activation of cyclopropanol for the quick
synthesis of discrete 1,6-diketones. The developed protocol
proceeds smoothly under mild conditions in short reaction
time and tolerates diverse functional groups. Notably, it is
facile for a wide range of substrates, including sterically
hindered ones. The preliminary experiments give insight into
the mechanism of the formation of 1,6-diketones via rhodium-
homoenolate. Moreover, the obtained 1,6-diketones can be
subjected to numerous transformations to furnish multiple
yield (Scheme 5b). Interestingly, 1, 6-diketone 5d, when
treated with hydrazine hydrate in the presence of AcOH,
underwent macrocyclization affording 7d in 61% yield
(Scheme 5c).
Inspired by the scope of transformation, a series of
mechanistic experiments were carried out. Initially, two
D
https://dx.doi.org/10.1021/acs.orglett.0c00967
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
valuable cyclic molecular architectures. This robust synthetic
strategy provides a useful tool for the synthesis of numerous
valuable molecules.
REFERENCES
■
(1) For selected recent reviews on transition-metal-catalyzed C−H
activation: (a) Wencel-Delord, J.; Glorius, F. C-H Bond Activation
Enables the Rapid Construction and Late-Stage Diversification of
Functional Molecules. Nat. Chem. 2013, 5, 369−375. (b) Rouquet,
G.; Chatani, N. Catalytic Functionalization of C(sp2)-H and C(sp3)-
H Bonds by Using Bidentate Directing Groups. Angew. Chem., Int. Ed.
2013, 52, 11726−11743. (c) Thirunavukkarasu, V. S.; Kozhushkov, S.
I.; Ackermann, L. C-H Nitrogenation and Oxygenation by Ruthenium
Catalysis. Chem. Commun. 2014, 50, 29−39. (d) Moselage, M.; Li, J.;
Ackermann, L. Cobalt-Catalyzed C-H Activation. ACS Catal. 2016, 6,
498−525. (e) Hummel, J. R.; Boerth, J. A.; Ellman, J. A. Transition-
Metal-Catalyzed C-H Bond Addition to Carbonyls, Imines, and
Related Polarized π Bonds. Chem. Rev. 2017, 117, 9163−9227.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00967.
Detailed experimental procedures, characterization data,
and X-ray crystallographic analysis of 2a (PDF)
FAIR data which includes the primary NMR FID files
for compounds 1d, 1e, 1g, 1h, 2a−2p, 4f, 5a−5k, and
7d (ZIP)
̈
(f) Sambiagio, C.; SchOnbauer, D.; Blieck, R.; DaoHuy, T.;
Pototschnig, G.; Schaaf, P.; Wiesinger, T.; Zia, M. F.; Wencel-
Accession Codes
Delord, J.; Besset, T.; Maes, B. U. W.; Schnurch, M. A comprehensive
̈
overview of directing groups applied in metal-catalysed C−H
functionalisation chemistry. Chem. Soc. Rev. 2018, 47, 6603−6743.
CCDC 1985325 contains 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(g) Gandeepan, P.; Muller, T.; Zell, D.; Cera, G.; Warratz, S.;
̈
Ackermann, L. 3d Transition Metals for C-H Activation. Chem. Rev.
2019, 119, 2192−2452 and the references cited therein.
(2) For selected recent reviews on transition-metal-catalyzed C−C
activation: (a) Murakami, M.; Matsuda, T. Metal-Catalysed Cleavage
of Carbon Carbon Bonds. Chem. Commun. 2011, 47, 1100−1105.
(b) Ruhland, K. Transition Metal-Mediated Cleavage and Activation
of C-C Single Bonds. Eur. J. Org. Chem. 2012, 2012, 2683−2706.
(c) Chen, F.; Wang, T.; Jiao, N. Recent Advances in Transition
Metal-Catalyzed Functionalization of Unstrained Carbon-Carbon
Bonds. Chem. Rev. 2014, 114, 8613−8661. (d) Souillart, L.;
Cramer, N. Catalytic C-C Bond Activations via Oxidative Addition
to Transition Metals. Chem. Rev. 2015, 115, 9410−9464. (e) Mur-
akami, M.; Ishida, N. Potential of Metal-Catalyzed C-C Single Bond
Cleavage for Organic Synthesis. J. Am. Chem. Soc. 2016, 138, 13759−
13769. (f) 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. (g) 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.
AUTHOR INFORMATION
Corresponding Author
■
P. C. Ravikumar − School of Chemical Sciences, National
Institute of Science Education and Research (NISER),
Bhubaneswar, HBNI 752050, Odisha, India; orcid.org/
0000-0002-5264-820X; Email: pcr@niser.ac.in
Authors
Bedadyuti Vedvyas Pati − School of Chemical Sciences,
National Institute of Science Education and Research (NISER),
Bhubaneswar, HBNI 752050, Odisha, India
Asit Ghosh − School of Chemical Sciences, National Institute of
Science Education and Research (NISER), Bhubaneswar, HBNI
752050, Odisha, India
̌
̌
̌
(3) (a) Korotvicka, A.; Císarova, I.; Roithova, J.; Kotora, M.
Synthesis of Aromatic Compounds by Catalytic C-C Bond Activation
of Biphenylene or Angular [3]Phenylene. Chem. - Eur. J. 2012, 18,
4200−4207. (b) Gu, Z.; Boursalian, G. B.; Gandon, V.; Padilla, R.;
Shen, H.; Timofeeva, T. V.; Tongwa, P.; Vollhardt, K. P. C.;
Yakovenko, A. A. Activated Phenacenes from Phenylenes by Nickel-
Catalyzed Alkyne Cycloadditions. Angew. Chem., Int. Ed. 2011, 50,
9413−9417. (c) Takano, H.; Kanyiva, K. S.; Shibata, T. Iridium-
Catalyzed Formal [4 + 1] Cycloaddition of Biphenylenes with
Alkenes Initiated by C-C Bond Cleavage for the Synthesis of 9,9-
Disubstituted Fluorenes. Org. Lett. 2016, 18, 1860−1863. (d) Xu, Y.;
Qi, X.; Zheng, P.; Berti, C. C.; Liu, P.; Dong, G. Deacylative
transformations of ketones via aromatization-promoted C−C bond
activation. Nature 2019, 567, 373−378.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00967
Author Contributions
†B.V.P. and A.G. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are thankful to NISER, Department of Atomic Energy
(DAE), Council for Scientific and Industrial Research (CSIR),
New Delhi (Grant 02(0256)/16/EMR II), and Science and
Engineering Research Board (SERB), New Delhi (Grant
EMRII/2017/001475) for financial support. A.G. thanks DAE,
and B.V.P. thanks DST-INSPIRE. We also thank Ranjit
Mishra, NISER Bhubaneswar, for GC analysis; Shreenibasa
NISER Bhubaneswar for solving single crystal data, and Sudip
Sau and Subhayan Chakraborty, NISER Bhubaneswar, for
instrumental help.
(4) 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.
(5) (a) Jun, C.-H.; Lee, H.; Moon, C. W.; Hong, H.-S. Cleavage of
Carbon-Carbon Triple Bond of Alkyne via Hydro-iminoacylation by
Rh (I) catalyst. J. Am. Chem. Soc. 2001, 123, 8600−8601. (b) Jiao, L.;
Yuan, C.; Yu, Z.-X. Tandem Rh (I)-Catalyzed [(5 + 2)+1]
Cycloaddition/Aldol Reaction for the Construction of Linear
Triquinane Skeleton: Total Syntheses of ( )-Hirsutene and ( )-1-
Desoxyhypnophilin. J. Am. Chem. Soc. 2008, 130, 4421−4430.
(c) Deng, L.; Chen, M.; Dong, G. Concise Synthesis of (−)-Cyclo-
clavine and (−)-5-epi-Cycloclavine via Asymmetric C-C Activation. J.
Am. Chem. Soc. 2018, 140, 9652−9658. (d) Bruffaerts, J.; Vasseur, A.;
Singh, S.; Masarwa, A.; Didier, D.; Oskar, L.; Perrin, L.; Eisenstein,
O.; Marek, I. Zirconocene-Mediated Selective C-C Bond Cleavage of
DEDICATION
■
Dedicated to Prof. P. Rajakumar, Department of Organic
Chemistry, University of Madras for his excellent teaching and
training to scores of Organic Chemists.
E
https://dx.doi.org/10.1021/acs.orglett.0c00967
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Strained Carbocycles: Scope and Mechanism. J. Org. Chem. 2018, 83,
3497−3515. (e) Ma, X. F.; Hazelden, I. R.; Langer, T.; Munday, R.
H.; Bower, J. F. Enantioselective aza-heck cyclizations of N-
(tosyloxy)carbamates: Synthesis of pyrrolidines and piperidines. J.
Am. Chem. Soc. 2019, 141, 3356−3360. (f) Li, S.; Shi, P.; Liu, R.-H.;
Hu, X.-H.; Loh, T.-P. Cobalt-Catalyzed N-O and C-C Bond Cleavage
in 1,2-Oxazetidines: Solvent Controlled C-H Aminomethylation and
Hydroxymethylation of Heteroarenes. Org. Lett. 2019, 21, 1602−
1606.
(6) Nanda, T.; Ravikumar, P. C. Org. Lett. 2020, 22, 1368.
(7) (a) Kulinkovich, O. G. The Chemistry of Cyclopropanols. Chem.
Rev. 2003, 103, 2597−2632. (b) Epstein, O. L.; Lee, S.; Cha, J. K.
Formation of Seven-Membered Carbocycles by the Use of Cyclo-
propyl Silyl Ethers as Homoenols. Angew. Chem., Int. Ed. 2006, 45,
4988−4991. (c) Lee, H. G.; Lysenko, I.; Cha, J. K. Stereoselective
Synthesis of 2,4,6-Trisubstituted Tetrahydropyrans by the Use of
Cyclopropanols as Homoenols. Angew. Chem., Int. Ed. 2007, 46,
3326−3328.
(8) (a) Oshino, H.; Nakamura, E.; Kuwajima, I. J. Org. Chem. 1985,
50, 2802−2804. (b) Kuwajima, I.; Nakamura, E. Metal Homoenolates
from Siloxycyclopropanes. Top. Curr. Chem. 1990, 155, 1−39.
(9) (a) Rosa, D.; Orellana, A. Palladium-catalyzed cross-coupling of
cyclopropanol-derived ketone homoenolates with aryl bromides.
Chem. Commun. 2013, 49, 5420−5422. (b) Parida, B. B.; Das, P.
P.; Niocel, M.; Cha, J. K. C-Acylation of Cyclopropanols: Preparation
of Functionalized 1,4-Diketones. Org. Lett. 2013, 15, 1780−1783.
(c) Cheng, K.; Walsh, P. J. Arylation of Aldehyde Homoenolates with
Aryl Bromides. Org. Lett. 2013, 15, 2298−2301. (d) Nithiy, N.;
Orellana, A. Palladium-Catalyzed Cross-Coupling of Benzyl Chlorides
with Cyclopropanol-Derived Ketone Homoenolates. Org. Lett. 2014,
16, 5854−5857. (e) Liu, H.; Fu, Z.; Gao, S.; Huang, Y.; Lin, A.; Yao,
H. Palladium-Catalyzed Hydroalkylation of Alkynes with Cyclo-
propanols: Access to γ,δ-Unsaturated Ketones. Adv. Synth. Catal.
2018, 360, 3171−3175. (f) Reding, A.; Jones, P. G.; Werz, D. B.
Intramolecular trans Carbocarbonation of Internal Alkynes by a
Cascade of Formal anti Carbopalladation/Cyclopropanol Opening.
Org. Lett. 2018, 20, 7266−7269.
(10) (a) Ye, Z.; Dai, M. An Umpolung Strategy for the Synthesis of
β-Aminoketones via Copper-Catalyzed Electrophilic Amination of
Cyclopropanols. Org. Lett. 2015, 17, 2190−2193. (b) Ye, Z.; Gettys,
K. E.; Shen, X.; Dai, M. Copper-Catalyzed Cyclopropanol Ring
Opening Csp3-Csp3 Cross-Couplings with (Fluoro)Alkyl Halides. Org.
Lett. 2015, 17, 6074−6077. (c) Li, Y.; Ye, Z.; Bellman, T. M.; Chi, T.;
Dai, M. Efficient Synthesis of β-CF3/SCF3-Substituted Carbonyls via
Copper-Catalyzed Electrophilic Ring-Opening Cross-Coupling of
Cyclopropanols. Org. Lett. 2015, 17, 2186−2189. (d) He, X.-P.;
Shu, Y.-J.; Dai, J.-J.; Zhang, W.-M.; Feng, Y.-S.; Xu, H.-J. Copper-
catalysed ring-opening trifluoromethylation of cyclopropanols. Org.
Biomol. Chem. 2015, 13, 7159−7163. (e) Zhang, H.; Wu, G.; Yi, H.;
Sun, T.; Wang, B.; Zhang, Y.; Dong, G.; Wang, J. Cu(I)-Catalyzed
Chemoselective Coupling of Cyclopropanols with Diazo Esters: Ring-
Opening C-C Bond Formations. Angew. Chem., Int. Ed. 2017, 56,
3945−3950. (f) Konik, Y. A.; Kudrjashova, M.; Konrad, N.; Kaabel,
S.; Jarving, I.; Lopp, M.; Kananovich, D. G. Two-step conversion of
carboxylic esters into distally fluorinated ketones via ring cleavage of
cyclopropanol intermediates: application of sulfinate salts as
fluoroalkylating reagents. Org. Biomol. Chem. 2017, 15, 4635−4643.
(g) Ye, Z.; Cai, X.; Li, J.; Dai, M. Catalytic cyclopropanol ring opening
for divergent syntheses of γ-butyrolactones and δ-ketoesters
containing all-carbon quaternary centers. ACS Catal. 2018, 8,
5907−5914.
[3 + 2] Cycloaddition between Cyclopropanols and Allenes. ACS
Catal. 2019, 9, 1973−1978. (c) Yang, J.; Sekiguchi, Y.; Yoshikai, N.
Cobalt-Catalyzed Enantioselective and Chemodivergent Addition of
Cyclopropanols to Oxabicyclic Alkenes. ACS Catal. 2019, 9, 5638−
5644.
(13) Mills, L. R.; Zhou, C.; Fung, E.; Rousseaux, S. A. L. Ni-
Catalyzed β-Alkylation of Cyclopropanol-Derived Homoenolates.
Org. Lett. 2019, 21, 8805−8809.
(14) (a) Ikura, K.; Ryu, I.; Ogawa, A.; Kambe, N.; Sonoda, N.
Rhodium(I)-Catalyzed Isomerization of Siloxycyclopropanes Leading
to Enol Silyl Ethers and Allyl Silyl Ethers. Tetrahedron Lett. 1989, 30,
6887−6890. (b) Zhou, X.; Yu, S.; Kong, L.; Li, X. Rhodium(III)-
Catalyzed Coupling of Arenes with Cyclopropanols via C-H
Activation and Ring Opening. ACS Catal. 2016, 6, 647−651.
(c) Zhou, X.-K.; Qi, Z.-S.; Yu, S.-J.; Kong, L.-H.; Li, Y.; Tian, W.-
F.; Li, X.-W. Synthesis of 2-Substituted Quinolines via Rhodium(III)-
Catalyzed C-H Activation of Imidamides and Coupling with
Cyclopropanols. Adv. Synth. Catal. 2017, 359, 1620−1625.
(d) Avullala, T.; Asgari, P.; Hua, Y.; Bokka, A.; Ridlen, S. G.; Yum,
K.; Dias, H. V. R.; Jeon, J. Umpolung α-Silylation of Cyclopropyl
Acetates via Low Temperature Catalytic C-C Activation. ACS Catal.
2019, 9, 402−408. (e) Meng, R.; Bi, S.; Jiang, Y.-Y.; Liu, Y. C−H
Activation versus Ring Opening and Inner-versus Outer-Sphere
Concerted Metalation−Deprotonation in Rh(III)-Catalyzed Oxida-
tive Coupling of Oxime Ether and Cyclopropanol: A Density
Functional Theory Study. J. Org. Chem. 2019, 84, 11150−11160.
(15) Kim, J.; Park, S.-W.; Baik, M.-H.; Chang, S. Complete Switch of
Selectivity in the C-H Alkenylation and Hydroarylation Catalyzed by
Iridium: The Role of Directing Groups. J. Am. Chem. Soc. 2015, 137,
13448−13451.
(16) (a) Ryu, I.; Ando, M.; Ogawa, A.; Murai, S.; Sonoda, N. A ß-
Metal Ketone Strategy. Reactions of Siloxycyclopropanes with
Silver(I) Tetrafluoroborate and Copper(II) Tetrafluoroborate Lead-
ing to 1,6-Diketones. J. Am. Chem. Soc. 1983, 105, 7192−7194.
(b) Ryu, I.; Matsumoto, K.; Kameyama, Y.; Ando, M.; Kusumoto, N.;
Ogawa, A.; Kambe, N.; Murai, S.; Sonoda, N. ß-Copper(II) Ketones.
Generation, Coupling, and Highly Stereoselective Trapping by
Electron-Deficient Acetylenes. J. Am. Chem. Soc. 1993, 115, 12330−
12339.
(17) (a) Tormo, J.; Hays, D. S.; Fu, G. C. Diastereoselective
Synthesis of ß-Amino Alcohols via Bu3SnH-Mediated Reductive
Cyclization of Carbonyl-Oxime Ethers. J. Org. Chem. 1998, 63, 201−
202. (b) Hays, D. S.; Fu, G. C. Bu3SnH-Mediated Pinacol Coupling of
1,5- and 1,6-Dicarbonyl Compounds: Synthetic and Mechanistic
Studies. J. Org. Chem. 1998, 63, 6375−6381. (c) Lee, J. C.; Ku, C. H.
Synthesis of, α,ω-Dicarboxylic Acid Dimethyl Esters from Cyclo-
alkanones. Synlett 2002, 1679−1680. (d) Larsen, M.; Kromann, H.;
Kharazmi, A.; Nielsen, S. F. Conformationally restricted anti-
plasmodial chalcones. Bioorg. Med. Chem. Lett. 2005, 15, 4858−
́
́
4861. (e) Paradas, M.; Campana, A. G.; Estevez, R. E.; Alvarez de
̃
́
Cienfuegos, L.; Jimenez, T.; Robles, R.; Cuerva, J. M.; Oltra, J. E.
Unexpected TiIII/Mn-Promoted Pinacol Coupling of Ketones. J. Org.
Chem. 2009, 74, 3616−3619. (f) Miyahara, Y.; Ito, Y. N. AlCl3-
Mediated Aldol Cyclocondensation of 1,6- and 1,7-Diones to
Cyclopentene and Cyclohexene Derivatives. J. Org. Chem. 2014, 79,
̈
̈
6801−6807. (g) Artunc, T.; Çetinkaya, Y.; Gocer, H.; Gulcin, I.;
Menzek, A.; Sahin, E.; Supuran, C. T. Synthesis of 4-[2-(3,4-
dimethoxybenzyl)cyclopentyl]-1,2-dimethoxybenzene Derivatives and
Evaluations of Their Carbonic Anhydrase Isoenzymes Inhibitory
Effects. Chem. Biol. Drug Des. 2016, 87, 594−607. (h) Sarkar, S.;
Banerjee, A.; Yao, W.; Patterson, E. V.; Ngai, M.-Y. Photocatalytic
Radical Aroylation of Unactivated Alkenes: Pathway to β-Function-
alized 1,4-, 1,6-, and 1,7-Diketones. ACS Catal. 2019, 9, 10358−
10364. (i) Bennett, N. B.; Stoltz, B. M. A Unified Approach to the
Daucane and Sphenolobane Bicyclo[5.3.0]decane Core: Enantiose-
lective Total Syntheses of Daucene, Daucenal, Epoxydaucenal B, and
14-paraAnisoyloxydauc-4,8-diene. Chem. - Eur. J. 2013, 19, 17745−
17750.
(11) Gyanchander, E.; Ydhyam, S.; Tumma, N.; Belmore, K.; Cha, J.
K. Mechanism of Ru(II)-Catalyzed Rearrangements of Allenyl- and
Alkynylcyclopropanols to Cyclopentenones. Org. Lett. 2016, 18,
6098−6101.
(12) (a) Yang, J.; Shen, Y.; Lim, Y. J.; Yoshikai, N. Divergent ring
opening coupling between cyclopropanols and alkynes under cobalt
catalysis. Chem. Sci. 2018, 9, 6928−6934. (b) Yang, J.; Sun, Q.;
Yoshikai, N. Cobalt-Catalyzed Regio- and Diastereoselective Formal
F
https://dx.doi.org/10.1021/acs.orglett.0c00967
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(18) (a) Enda, J.; Matsutani, T.; Kuwajima, I. Stoichiometric
generation of magnesium homoenolate equivalents from acyltrime-
thylsilanes. Synthesis of 1,6-diketdne derivatives. Tetrahedron Lett.
1984, 25, 5307−5310. (b) Brown, H. C.; Racherla, U. S.; Singh, S. M.
A general, highly efficient synthesis of 1, 4-, 1, 5-, and 1, 6-diketones.
Synthesis 1984, 1984, 922−924. (c) Nishinaga, A.; Rindo, K.;
Matsuura, T. A Convenient Synthesis of Acyclic 1, n-Diketones (n
= 5−8) from 2-t-Butylperoxycycloalkanones. Synthesis 1986, 1986,
1038−1041. (d) Saikia, A.; Chetia, A.; Bora, U.; Boruah, R. C. A
Facile Synthesis of 1,6-Diketones via a Three-Component Michael
Addition Reaction. Synlett 2003, 10, 1506−1508. (e) Wang, X.; Liu,
M.; Xu, L.; Wang, Q.; Chen, J.; Ding, J.; Wu, H. Palladium-Catalyzed
Addition of Potassium Aryltrifluoroborates to Aliphatic Nitriles:
Synthesis of Alkyl Aryl Ketones, Diketone Compounds, and 2-
Arylbenzo[b]furans. J. Org. Chem. 2013, 78, 5273−5281.
(19) Shi, Y.-C.; Duan, H.-Y. , Two Seven-Membered Heterocycles
with 1,2-Diaza Ring N Atoms: 3,5,7-Triphenyl-1,2-Diazacyclohepta-
1(7),2-Diene And 3,7-Bis(2-Hydroxyphenyl)-5-Phenyl-1,2-Diazacy-
clohepta-1(7),2-Diene. Acta Crystallogr., Sect. C: Cryst. Struct.
Commun. 2013, 69, 1177−1180.
(20) Bay, K. L.; Yang, Y.; Houk, K. N. Multiple Roles of Silver Salts
in Palladium-Catalyzed C-H Activations. J. Organomet. Chem. 2018,
864, 19−25.
G
https://dx.doi.org/10.1021/acs.orglett.0c00967
Org. Lett. XXXX, XXX, XXX−XXX