Iron-Catalyzed Ortho C-H Homoallylation of Aromatic Ketones with Methylenecyclopropanes

Article abstract of DOI:10.1021/jacs.1c00237

We report here a C-H homoallylation reaction of aromatic ketones with methylenecyclopropanes (MCPs) only using a catalytic amount of Fe(PMe3)4. A variety of aromatic ketones and MCPs are applicable to the reaction to form ortho-homoallylated aromatic ketones selectively via regioselective scission of the three-membered rings. The homoallylated products are amenable to further elaborations, providing functionalized 1,2-dihydronaphthalenes.

Full text of DOI:10.1021/jacs.1c00237

pubs.acs.org/JACS
Communication
Iron-Catalyzed Ortho C−H Homoallylation of Aromatic Ketones with
Methylenecyclopropanes
Naoki Kimura, Shiori Katta, Yoichi Kitazawa, Takuya Kochi, and Fumitoshi Kakiuchi*
Cite This: J. Am. Chem. Soc. 2021, 143, 4543−4549
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: We report here a C−H homoallylation reaction of aromatic ketones with methylenecyclopropanes (MCPs) only
using a catalytic amount of Fe(PMe3)4. A variety of aromatic ketones and MCPs are applicable to the reaction to form ortho-
homoallylated aromatic ketones selectively via regioselective scission of the three-membered rings. The homoallylated products are
amenable to further elaborations, providing functionalized 1,2-dihydronaphthalenes.
ransition-metal-catalyzed C−H functionalizations of
T
arenes have been extensively investigated in the past
two decades, and it has become possible to directly substitute
hydrogen atoms on aromatic rings with various classes of
functional groups including those containing a reactive
functional group.1,2 In addition, increasing demand for
sustainable chemical processes has prompted researchers to
develop reactions using earth-abundant metals,3 and in this
context, C−H functionalizations using catalysts of iron, the
most abundant transition metal in the crust, have been
extensively studied.4
Alkenes are one of the most versatile functional groups in
organic synthesis, and numerous methods have been
developed for direct introduction of alkenyl5 and allyl6 groups.
In contrast, the corresponding C−H homoallylation has been
challenging due to facile isomerization of the homoallylation
products and β-hydride elimination of homoallylmetal
intermediates into metal hydrides and 1,3-dienes. As a result,
limited types of homoallylating agents have been explored.
Alkyl halides such as homoallyl and cyclopropylmethyl halides
have been mostly used for this purpose (Figure 1a),7 but only a
few homoallyl-type substituents have been introduced on
aromatic rings. The use of 1,6-enynes has also been reported
for introduction of homoallyl groups containing a five-
membered ring (Figure 1b).8 However, development of
convenient methods for C−H homoallylation is still desired.
We envisioned that methylenecyclopropanes (MCPs),9 which
are prepared in two steps from alkenes, would be suitable
coupling partners in the C−H homoallylation. The use of
MCPs in arene homoallylation has only been reported for a
Friedel−Crafts type method10 and has not been explored for
reactions via C−H bond cleavage by transition metal catalysts.
Reported examples of C−H functionalization with MCPs have
provided other types of products such as simple cyclopropyl-
methylation,11 cyclization,12 or alkenylation/dienylation13
products.
Figure 1. C−H homoallylation reactions.
regioselectivity just by reacting aromatic ketones with MCPs in
the presence of a catalytic amount of Fe(PMe3)4. The
homoallylation products were applicable to facile synthesis of
functionalized 1,2-dihydronaphthalenes.
We began our investigation of C−H homoallylation using
Fe(PMe3)4 catalyst,15,16 which our group found to work in a
C−H/olefin coupling in 2017.15 When the reaction of p-
trifluoromethylpivalophenone (1a) with 1.5 equiv of 2-phenyl-
1-methylenecyclopropane (2a) was carried out using 5 mol %
Fe(PMe3)4 (3) in THF at 70 °C for 20 h, homoallylation of
the ortho C−H bond proceeded to give product 4aa in 57%
NMR yield (Table 1, entry 1). This reaction did not give
Received: January 8, 2021
Published: March 17, 2021
Here we report that direct introduction of a variety of β-
substituted homoallyl groups can be achieved for an iron-
catalyzed reaction of aromatic ketones with MCPs (Figure
1c).14 The ortho C−H homoallylation proceeds with complete
https://doi.org/10.1021/jacs.1c00237
J. Am. Chem. Soc. 2021, 143, 4543−4549
© 2021 American Chemical Society
4543

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
a
Table 1. Selected Optimization Results
Table 2. Iron-Catalyzed C−H Homoallylation of
a
Pivalophenones 1 with Various MCPs 2
temp
2a
conversion of 1a yield of 4aa
b
b
b
R1
2
R2
R3
4, yield (%)
entry
solvent
THF
DMF
toluene
hexane
cyclohexane
none
cyclohexane
cyclohexane
(°C)
(equiv)
(%)
(%)
entry
1
1
2
3
4
5
6
70
70
70
70
70
70
40
40
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.1
64
26
70
81
87
57
87
97
57
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
H
2b
2c
2d
2e
2f
2g
2h
2i
2j
2j
2k
2l
2-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
2-naphthyl
CH2CH2Ph
C8H17
H
H
H
H
H
H
H
H
Ph
Ph
Me
Me
4ab, 86
4ac, 75
4ad, 87
4ae, 79
4af, 72
4ag, 95
4ah, 96
4ai, 86
20
60
75
79
38
86
c
7
c
d
8
97 (93)
CH2OBn
Ph
a
9
4aj, 26 (83)
4bj, 74
Reaction conditions: 1 (0.3 mmol), 2 (0.45 or 0.33 mmol), 3 (0.015
b
mmol), solvent (0.3 mL, if any). Determined by 1H NMR
10
11
12
Ph
Ph
c
d
spectroscopy. Performed in 0.4 mL of cyclohexane. Isolated yield.
H
H
4bk, 78
4bl, 78
c
CH2CH2Ph
a
Reaction conditions: 1 (0.3 mmol), 2 (0.33 mmol), 3 (0.015 mmol),
observable amounts of other coupling products such as
cyclopropylmethylation products, obtained in several Ru-
catalyzed reactions,11a−c,17 and the phenyl group is selectively
installed at the 2-position of the homoallyl group, which
indicates the regioselective opening of the cyclopropyl ring. It
is also noteworthy that neither isomerization of the terminal
olefin moiety of product 4aa to an internal one nor subsequent
C−H alkylation with the terminal olefin moiety of 4aa
occurred during the reaction. Screening of solvents was then
conducted. Reduction of the yield to 20% was observed for the
reaction in DMF (entry 2). Toluene (entry 3) and hexane
(entry 4) were found to be effective as a solvent for the
reaction, but cyclohexane (entry 5) gave the highest yield of
product 4aa. In our previous study of the Fe(PMe3)4-catalyzed
C−H/olefin coupling of aromatic ketones, the highest yield
was obtained under neat reaction conditions,15 but the C−H/
MCP coupling under neat conditions lowered the conversion
of 1a and the yield of product 4aa (entry 6). Optimization of
the reaction temperature and the solvent volume improved the
yield to 86% (entry 7), and finally, the use of 1.1 equiv of 2a
was found to give product 4aa in 97% NMR yield (entry 8).18
The reactions of 1a with 2a were also tested using Ru, Rh, and
Ir catalysts1,8a,19 which are known to cleave ortho C−H bonds
of aromatic ketones by oxidative addition, but no coupling
product was obtained for these cases.20
b
40 °C, 20 h. Isolated yields are shown, and an NMR yield is shown
in parentheses. Performed with 10 mol % 3.
c
monosubstituted MCPs (2b−2i) provided three-membered
ring opening products 4ab−4ai exclusively, and any other
coupling product could not be detected (entries 1−8).
In addition to monosubstituted MCPs, disubstituted MCPs
2j−l were found to be applicable to this reaction. The reaction
using 2j gave homoallylation product 4aj in 83% NMR yield
along with the 5% NMR yield of cyclopropylmethylation
product 5aj with conservation of the cyclopropane ring (entry
9).21,22 4aj was isolated only in 26% yield, because it was
difficult to separate 4aj from isomer 5aj.23 Disubstituted MCP
2j was also used for the reaction of pivalophenone (1b) to give
product 4bj along with the 5% NMR yield of cyclopropyl-
methylation product 5bj. It was revealed that 4bj could be
easily separated from 5bj and isolated in 74% yield (entry 10).
The reaction of 1b with other disubstituted MCPs (2k, l)
proceeded to give 4bk and 4bl in both 78% yields (entries 11,
12). Finally, trans-2,3-diphenyl-1-methylenecyclopropane
(2m) also reacted with 1a to give a product possessing phenyl
groups at the 1- and 2-positions of the homoallyl group (4am),
albeit in low yield (eq 1).24
With the optimized reaction conditions in hand, the
substrate scope for the C−H homoallylation was explored
using various MCPs and aromatic ketones. The reactions were
first performed using p-trifluoromethylpivalophenone (1a)
with various MCPs (Table 2, entries 1−9). The reaction of
1a proceeded with MCPs containing electron-donating
(methyl and methoxy) (2b, c) and -withdrawing (fluoro and
chloro) groups (2d, e), and the corresponding homoallylation
products 4ab−4ae were obtained in high yields (entries 1−4).
The use of 2-naphthyl-substituted MCP (2f) provided product
4af in 72% yield (entry 5). MCPs having an alkyl substituent
(2g, h) showed high reactivity for this reaction to afford
products 4ag and 4ah in 95% and 96% yields, respectively
(entries 6, 7). Moreover, the reaction with 2i, which contains a
benzyl ether moiety, provided homoallylation product 4ai in
86% yield (entry 8). It is worth noting that all of the
The C−H homoallylation were also examined with various
aromatic ketones (Table 3).25 Pivalophenone derivatives
bearing ester (1c) and cyano (1d) functional groups at the
para position delivered the corresponding homoallylation
products 4ca−4da. The reaction of m-trifluoromethylpivalo-
phenone (1e) took place exclusively at a sterically less
hindered ortho position to produce product 4ea in 84%
yield, while a pivalophenone derivative bearing a methyl group
4544
https://doi.org/10.1021/jacs.1c00237
J. Am. Chem. Soc. 2021, 143, 4543−4549

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
tetralone derivatives (1l, 1m) and a benzosuberone derivative
(1n), were good substrates for this transformation as well.
In addition to alkyl aryl ketones, benzophenone (1o) proved
to be a suitable substrate for the C−H homoallylation reaction,
providing product 4oa in 70% yield. In the reaction of 2-
methylbenzophenone (1p), the homoallyl group was selec-
tively introduced to the unsubstituted benzene ring and the
second C−H homoallylation product was not observed.
Furthermore, benzophenones containing halogens at the para
positions (1q−1s), as well as those containing electron-
donating methyl groups (1t), were found to be applicable to
this transformation. In some cases, toluene was used as a
solvent due to the poor solubility of aromatic ketones in
cyclohexane.
Table 3. Iron-Catalyzed C−H Homoallylation of Various
a
Aromatic Ketones 1 with MCPs 2
Homoallylated aromatic ketones 4 can be converted to 1,2-
dihydronaphthalenes26 by carbonyl-olefin metathesis.27 The
reaction of 4oa with Schrock’s Mo complex 6 led to the
formation of the corresponding 1,2-dihydronaphthalene 7oa in
74% yield via the ring-closing metathesis (eq 2). Likewise,
carbonyl-olefin metathesis of 4am proceeded to give the
corresponding 1,2-diphenyl-1,2-dihydronaphthalene.28
To gain insights into the reaction mechanism, a deuterated
pivalophenone 1b-d5 was reacted with 2j for 1 h (Figure 2a).
1
2
According to the H and H NMR spectra of the recovered
starting materials, no H/D exchange was observed between 1b-
d5 and 2j, suggesting that not 2,1-insertion but 1,2-insertion of
2j only took place. Moreover, this experiment gave product
4bj-d5 in 7% yield, in which there was almost quantitative
deuterium incorporation (98% D) into the methine carbon.
The kinetic isotope effects (KIEs) on the C−H homoallylation
were examined, and the KIE values determined from the
competitive and parallel experiments were 1.9 and 1.7,
respectively (Figure 2b, c).
Based on our mechanistic considerations (Figure 2a−c) and
31P NMR monitoring,29 a possible catalytic cycle is proposed
as shown in Figure 2d. The strong back-bonding ability of the
MCP30 may enable its coordination to Fe(0) species A to
afford MCP complex B. Then, oxidative addition of the ortho
C−H bond of the aromatic ketone 1 to B occurs to provide
intermediate C, and regioselective hydrometalation of the
MCP gives cyclopropylmethyliron intermediate D. Subsequent
β-carbon elimination at the less congested C−C bond provides
the homoallyliron intermediate E, and finally, reductive
elimination affords the homoallylation product 4 along with
regenerated iron catalyst A. The KIE values >1.7 indicate that
the C−H bond cleavage or the hydrometalation31 is the
turnover-limiting step.
a
Reaction conditions: 1 (0.3 mmol), 2 (0.33 mmol), 3 (0.015 mmol),
40 °C, 20 h. Isolated yields are shown, and an NMR yield is shown in
parentheses. Performed with 10 mol % 3. Reaction conditions: 1
(0.6 mmol), 2 (0.3 mmol), 3 (0.015 mmol), 70 °C, 20 h. Performed
with 20 mol % 3. Reaction conditions: 1 (0.6 mmol), 2 (0.3 mmol),
b
c
d
e
f
3 (0.015 mmol), 40 °C, 20 h. Toluene was used as a solvent.
at the ortho position (1f) failed to give product 4fj. Changing
the alkyl substituent at R2 to a less bulky cyclohexyl group (1g)
led to the formation of a small amount of the dihomoallylation
product. After an additional screening, the yield of product 4gl
was improved by performing the reaction at 70 °C using 2
equiv of 1g. Aside from 1g, other alkyl aryl ketones proved to
be viable substrates, as exemplified with isobutyrophenone
(1h), propiophenone (1i), acetophenone (1j), and 2′-
methylacetophenone (1k), which gave products 4hl−4kl in
71−88% yields. Moreover, cyclic aromatic ketones, such as α-
In summary, an iron-catalyzed ortho C−H homoallylation of
aromatic ketones was developed using MCPs under mild,
additive-free reaction conditions. Facile, regioselective cleavage
of the three-membered ring as well as the ortho C−H bond
enabled the selective formation of the homoallylation products.
4545
https://doi.org/10.1021/jacs.1c00237
J. Am. Chem. Soc. 2021, 143, 4543−4549

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
AUTHOR INFORMATION
■
Corresponding Author
Fumitoshi Kakiuchi − Department of Chemistry, Faculty of
Science and Technology, Keio University, Yokohama,
Kanagawa 223-8522, Japan; orcid.org/0000-0003-
2605-4675; Email: kakiuchi@chem.keio.ac.jp
Authors
Naoki Kimura − Department of Chemistry, Faculty of Science
and Technology, Keio University, Yokohama, Kanagawa
223-8522, Japan
Shiori Katta − Department of Chemistry, Faculty of Science
and Technology, Keio University, Yokohama, Kanagawa
223-8522, Japan
Yoichi Kitazawa − Department of Chemistry, Faculty of
Science and Technology, Keio University, Yokohama,
Kanagawa 223-8522, Japan
Takuya Kochi − Department of Chemistry, Faculty of Science
and Technology, Keio University, Yokohama, Kanagawa
223-8522, Japan; orcid.org/0000-0002-5491-0566
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c00237
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by JSPS KAKENHI Grant
Numbers JP15H05839 (Middle Molecular Strategy) and
JP17K19126 and JST CREST Grant Number JPMJCR20R1.
T.K. is also grateful for the support by JSPS KAKENHI Grant
Number JP18H04271 (Precisely Designed Catalysts with
Customized Scaffolding). N.K. is also grateful for support by
the Japan Society for the Promotion of Science (JSPS) for a
Research Fellowship for Young Scientists (JP19J12813).
REFERENCES
■
(1) (a) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.;
Sonoda, M.; Chatani, N. Efficient Catalytic Addition of Aromatic
Carbon−Hydrogen Bonds to Olefins. Nature 1993, 366, 529−531.
(b) Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda, M.;
Chatani, N.; Murai, S. Catalytic Addition of Aromatic Carbon−
Hydrogen Bonds to Olefins with the Aid of Ruthenium Complexes.
Bull. Chem. Soc. Jpn. 1995, 68, 62−83. (c) Kakiuchi, F.; Murai, S.
Catalytic C−H/Olefin Coupling. Acc. Chem. Res. 2002, 35, 826−834.
(2) Recent reviews on C−H functionalization: (a) Chen, Z.; Wang,
B.; Zhang, J.; Yu, W.; Liu, Z.; Zhang, Y. Transition Metal-Catalyzed
C−H Bond Functionalizations by the Use of Diverse Directing
Groups. Org. Chem. Front. 2015, 2, 1107−1295. (b) Zhu, R.-Y.;
Farmer, M. E.; Chen, Y.-Q.; Yu, J.-Q. A Simple and Versatile Amide
Directing Group for C−H Functionalizations. Angew. Chem., Int. Ed.
2016, 55, 10578−10599. (c) Huang, Z.; Lim, H. N.; Mo, F.; Young,
M. C.; Dong, G. Transition Metal-Catalyzed Ketone-Directed or
Mediated C−H Functionalization. Chem. Soc. Rev. 2015, 44, 7764−
7786. (d) Gensch, T.; Hopkinson, M. N.; Glorius, F.; Wencel-Delord,
J. Mild Metal-Catalyzed C−H Activation: Examples and Concepts.
Chem. Soc. Rev. 2016, 45, 2900−2936. (e) Hartwig, J. F. Evolution of
C−H Bond Functionalization from Methane to Methodology. J. Am.
Chem. Soc. 2016, 138, 2−24. (f) Dong, Z.; Ren, Z.; Thompson, S. J.;
Xu, Y.; Dong, G. Transition-Metal-Catalyzed C−H Alkylation Using
Alkenes. Chem. Rev. 2017, 117, 9333−9403. (g) Sambiagio, C.;
Schönbauer, D.; Blieck, R.; Dao-Huy, T.; Pototschnig, G.; Schaaf, P.;
Wiesinger, T.; Zia, M. F.; Wencel-Delord, J.; Besset, T.; Maes, B. U.
Figure 2. Mechanistic considerations of the iron-catalyzed C−H
homoallylation.
A wide range of aromatic ketones and MCPs are applicable to
the reaction. 1,2-Dihydronaphthalene derivatives were synthe-
sized in two steps from readily accessible aromatic ketones
using this method. The results of the deuterium-labeling
experiments revealed that the ortho hydrogen was transferred
to the methine carbon of the vinyl group in the product, and
either the C−H bond cleavage or the hydrometalation is the
turnover-limiting step for the coupling with MCPs.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c00237.
Full experimental details and characterization data
(PDF)
W.; Schnu
̈
rch, M. A Comprehensive Overview of Directing Groups
4546
https://doi.org/10.1021/jacs.1c00237
J. Am. Chem. Soc. 2021, 143, 4543−4549

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
Applied in Metal-Catalysed C−H Functionalisation Chemistry. Chem.
Soc. Rev. 2018, 47, 6603−6743.
Noguchi, K.; Hirano, M. Highly Regio-, Diastereo-, and Enantiose-
lective [2+2+2] Cycloaddition of 1,6-Enynes with Electron-Deficient
Ketones Catalyzed by a Cationic RhI/H8-binap Complex. Angew.
Chem., Int. Ed. 2008, 47, 1312−1316. (c) Santhoshkumar, R.;
Mannathan, S.; Cheng, C.-H. Cobalt-Catalyzed Hydroarylative
Cyclization of 1,6-Enynes with Aromatic Ketones and Esters via C−
H Activation. Org. Lett. 2014, 16, 4208−4211. (d) Whyte, A.; Torelli,
A.; Mirabi, B.; Prieto, L.; Rodríguez, J. F.; Lautens, M. Cobalt-
Catalyzed Enantioselective Hydroarylation of 1,6-Enynes. J. Am.
Chem. Soc. 2020, 142, 9510−9517. C−H homoallylation of aromatic
aldehydes using 1,6-enynes: (e) Santhoshkumar, R.; Mannathan, S.;
Cheng, C.-H. Ligand-Controlled Divergent C−H Functionalization of
Aldehydes with Enynes by Cobalt Catalysts. J. Am. Chem. Soc. 2015,
137, 16116−16120.
(3) 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.
(4) Shang, R.; Ilies, L.; Nakamura, E. Iron-Catalyzed C−H Bond
Activation. Chem. Rev. 2017, 117, 9086−9139.
(5) Recent reviews on C−H alkenylation: (a) Kozhushkov, S. I.;
Ackermann, L. Ruthenium-Catalyzed Direct Oxidative Alkenylation of
Arenes through Twofold C−H Bond Functionalization. Chem. Sci.
2013, 4, 886−896. (b) Zhou, L.; Lu, W. Towards Ideal Synthesis:
Alkenylation of Aryl C−H Bonds by a Fujiwara-Moritani Reaction.
Chem. - Eur. J. 2014, 20, 634−642. (c) Manikandan, R.; Jeganmohan,
M. Recent Advances in the Ruthenium-Catalyzed Hydroarylation of
Alkynes with Aromatics: Synthesis of Trisubstituted Alkenes. Org.
Biomol. Chem. 2015, 13, 10420−10436. (d) Boyarskiy, V. P.;
Ryabukhin, D. S.; Bokach, N. A.; Vasilyev, A. V. Alkenylation of
Arenes and Heteroarenes with Alkynes. Chem. Rev. 2016, 116, 5894−
5986. (e) Manikandan, R.; Jeganmohan, M. Recent Advances in the
Ruthenium(II)-Catalyzed Chelation-Assisted C−H Olefination of
Substituted Aromatics, Alkenes and Heteroaromatics with Alkenes via
the Deprotonation Pathway. Chem. Commun. 2017, 53, 8931−8947.
(f) Petrini, M. Regioselective Direct C-Alkenylation of Indoles. Chem.
- Eur. J. 2017, 23, 16115−16151. (g) Hu, Y.; Wang, C. Manganese-
Catalyzed C−H Olefination Reactions. ChemCatChem 2019, 11,
1167−1174. (h) Koubachi, J.; El Brahmi, N.; Guillaumet, G.; El
Kazzouli, S. Oxidative Alkenylation of Fused Bicyclic Heterocycles.
Eur. J. Org. Chem. 2019, 2019, 2568−2586.
(9) Reviews on transformation of MCPs: (a) Nakamura, I.;
Yamamoto, Y. Transition Metal-Catalyzed Reactions of Methylene-
cyclopropanes. Adv. Synth. Catal. 2002, 344, 111−129. (b) Rubin, M.;
Rubina, M.; Gevorgyan, V. Transition Metal Chemistry of Cyclo-
propenes and Cyclopropanes. Chem. Rev. 2007, 107, 3117−3179.
(c) Masarwa, A.; Marek, I. Selectivity in Metal-Catalyzed Carbon−
Carbon Bond Cleavage of Alkylidenecyclopropanes. Chem. - Eur. J.
2010, 16, 9712−9721. (d) Pellissier, H. Recent Developments in the
Reactivity of Methylene- and Alkylidenecyclopropane Derivatives.
Tetrahedron 2010, 66, 8341−8375. (e) Aïssa, C. Transition-Metal-
Catalyzed Rearrangements of Small Cycloalkanes: Regioselectivity
Trends in β-Carbon Elimination Reactions. Synthesis 2011, 2011,
3389−3407. (f) Pellissier, H. Recent Developments in the Synthesis
and Reactivity of Methylene- and Alkylidenecyclopropane Derivatives.
Tetrahedron 2014, 70, 4991−5031. (g) Brandi, A.; Cicchi, S.;
Cordero, F. M.; Goti, A. Progress in the Synthesis and Trans-
formations of Alkylidenecyclopropanes and Alkylidenecyclobutanes.
Chem. Rev. 2014, 114, 7317−7420. (h) Marek, I.; Masarwa, A.;
Delaye, P.-O.; Leibeling, M. Selective Carbon−Carbon Bond
Cleavage for the Stereoselective Synthesis of Acyclic Systems.
Angew. Chem., Int. Ed. 2015, 54, 414−429. (i) Wang, F.; Yu, S.; Li,
X. Transition Metal-Catalysed Couplings between Arenes and
Strained or Reactive Rings: Combination of C−H Activation and
Ring Scission. Chem. Soc. Rev. 2016, 45, 6462−6477. (j) 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. (k) Shah, T. A.; De,
P. B.; Pradhan, S.; Banerjee, S.; Punniyamurthy, T. Exploiting
Strained Rings in Chelation Guided C−H Functionalization:
Integration of C−H Activation with Ring Cleavage. Chem. - Asian J.
2019, 14, 4520−4533.
(6) Review on C−H allylation: Mishra, N. K.; Sharma, S.; Park, J.;
Han, S.; Kim, I. S. Recent Advances in Catalytic C(sp2)−H Allylation
Reactions. ACS Catal. 2017, 7, 2821−2847.
(7) Chelation-assisted C−H homoallylation using alkyl halides:
(a) Aihara, Y.; Chatani, N. Nickel-Catalyzed Direct Alkylation of C−
H Bonds in Benzamides and Acrylamides with Functionalized Alkyl
Halides via Bidentate-Chelation Assistance. J. Am. Chem. Soc. 2013,
135, 5308−5311. (b) Chen, K.; Hu, F.; Zhang, S.-Q.; Shi, B.-F.
Pd(II)-Catalyzed Alkylation of Unactivated C(sp3)−H Bonds:
Efficient Synthesis of Optically Active Unnatural α-Amino Acids.
Chem. Sci. 2013, 4, 3906−3911. (c) Wu, X.; Zhao, Y.; Ge, H. Nickel-
Catalyzed Site-Selective Alkylation of Unactivated C(sp3)−H Bonds.
J. Am. Chem. Soc. 2014, 136, 1789−1792. (d) Monks, B. M.; Fruchey,
E. R.; Cook, S. P. Iron-Catalyzed C(sp2)−H Alkylation of
Carboxamides with Primary Electrophiles. Angew. Chem., Int. Ed.
2014, 53, 11065−11069. (e) Ilies, L.; Matsubara, T.; Ichikawa, S.;
Asako, S.; Nakamura, E. Iron-Catalyzed Directed Alkylation of
Aromatic and Olefinic Carboxamides with Primary and Secondary
Alkyl Tosylates, Mesylates, and Halides. J. Am. Chem. Soc. 2014, 136,
13126−13129. (f) Aihara, Y.; Wuelbern, J.; Chatani, N. The
Nickel(II)-Catalyzed Direct Benzylation, Allylation, Alkylation, and
Methylation of C−H Bonds in Aromatic Amides Containing an 8-
Aminoquinoline Moiety as the Directing Group. Bull. Chem. Soc. Jpn.
2015, 88, 438−446. (g) Ruan, Z.; Lackner, S.; Ackermann, L. A
General Strategy for the Nickel-Catalyzed C−H Alkylation of
Anilines. Angew. Chem., Int. Ed. 2016, 55, 3153−3157. (h) Cera,
G.; Haven, T.; Ackermann, L. Expedient Iron-Catalyzed C−H
Allylation/Alkylation by Triazole Assistance with Ample Scope.
Angew. Chem., Int. Ed. 2016, 55, 1484−1488. (i) Liu, W.; Cera, G.;
Oliveira, J. C. A.; Shen, Z.; Ackermann, L. MnCl2-Catalyzed C−H
Alkylations with Alkyl Halides. Chem. - Eur. J. 2017, 23, 11524−
11528. (j) Ghorai, D.; Finger, L. H.; Zanoni, G.; Ackermann, L.
Bimetallic Nickel Complexes for Aniline C−H Alkylations. ACS Catal.
2018, 8, 11657−11662. (k) Shen, Z.; Huang, H.; Zhu, C.; Warratz, S.;
Ackermann, L. MnCl2-Catalyzed C−H Alkylation on Azine Hetero-
cycles. Org. Lett. 2019, 21, 571−574.
(10) Huang, J.-W.; Shi, M. Lewis Acid BF3·OEt2-Catalyzed Friedel−
Crafts Reaction of Methylenecyclopropanes with Arenes. Tetrahedron
Lett. 2003, 44, 9343−9347.
(11) (a) Kozhushkov, S. I.; Yufit, D. S.; Ackermann, L. Ruthenium-
Catalyzed Hydroarylations of Methylenecyclopropanes: Mild C−H
Bond Functionalizations with Conservation of Cyclopropane Rings.
Org. Lett. 2008, 10, 3409−3412. (b) Ackermann, L.; Kozhushkov, S.
I.; Yufit, D. S. Ruthenium-Catalyzed Hydroarylation of Methylene-
cyclopropanes through C−H Bond Cleavage: Scope and Mechanism.
Chem. - Eur. J. 2012, 18, 12068−12077. (c) Schinkel, M.; Wallbaum,
J.; Kozhushkov, S. I.; Marek, I.; Ackermann, L. Carboxylate Assistance
for Catalyzed Hydroarylations of Methylenecyclopropanes. Org. Lett.
2013, 15, 4482−4484. (d) Timmerman, J. C.; Schmitt, W. W.;
Widenhoefer, R. A. Gold-Catalyzed Intermolecular, anti-Markovnikov
Hydroarylation of Methylenecyclopropanes with Indoles. Org. Lett.
2016, 18, 4966−4969.
(12) (a) Zhou, H.; Huang, X.; Chen, W. First Tandem Free-Radical
Cyclization Reaction of Alkylenecyclopropanes: A Novel and Efficient
Method for the Preparation of 2-(3,4-Dihydronaphthalen-2-yl)-
malonic Acid Diethyl Esters. J. Org. Chem. 2004, 69, 5471−5472.
(b) Huang, X.; Yu, L. The Reaction of Alkylenecyclopropanes and
Diethyl Phosphite: A Novel Method for the Preparation of Diethyl
3,4-Dihydro-2-naphthylphosphonates and 3-Butenyl Ethyl Phos-
phates. Synlett 2005, 2005, 2953−2957. (c) Yu, L.; Huang, X.; Xie,
(8) C−H homoallylation of aromatic ketones using 1,6-enynes:
(a) Tsuchikama, K.; Kuwata, Y.; Tahara, Y.; Yoshinami, Y.; Shibata, T.
Rh-Catalyzed Cyclization of Diynes and Enynes Initiated by
Carbonyl-Directed Activation of Aromatic and Vinylic C−H Bonds.
Org. Lett. 2007, 9, 3097−3099. (b) Tanaka, K.; Otake, Y.; Sagae, H.;
4547
https://doi.org/10.1021/jacs.1c00237
J. Am. Chem. Soc. 2021, 143, 4543−4549

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
M. Synthesis of 3-Phenylsulfanyl-1,2-dihydronaphthalenes from
Methylenecyclopropanes and Benzenethiol. Synlett 2006, 2006,
423−426. (d) Fu, W.-J.; Huang, X. Mn(III)-Based Oxidative Tandem
Free-Radical Cyclizations of Methylenecyclopropanes with Substi-
tuted Dicarbonyl Compounds. J. Organomet. Chem. 2007, 692, 740−
Transition-metal-catalyzed isomerization of MCPs into 1,3-dienes:
(a) Nishihara, Y.; Yoda, C.; Osakada, K. Hydrido-Rhodium(I) and
-Iridium(I) Complex Promoted Ring-Opening Isomerization of
Unsymmetrically Substituted Methylenecyclopropanes into 1,3-
Dienes. Structures of Intermediates and Reaction Pathways. Organo-
metallics 2001, 20, 2124−2126. (b) Nishihara, Y.; Yoda, C.; Itazaki,
M.; Osakada, K. Selective C−C Bond Activation of 2-Aryl-1-
methylenecyclopropanes Promoted by Ir(I) and Rh(I) Hydrido
Complexes. Mechanism of Ring-Opening Isomerization of the
Strained Molecules. Bull. Chem. Soc. Jpn. 2005, 78, 1469−1480.
(c) Shi, M.; Wang, B.-Y.; Huang, J.-W. Palladium-Catalyzed
Isomerization of Methylenecyclopropanes in Acetic Acid. J. Org.
Chem. 2005, 70, 5606−5610. (d) Shirakura, M.; Suginome, M.
Nickel-Catalyzed, Regio- and Stereoselective Hydroalkynylation of
Methylenecyclopropanes with Retention of the Cyclopropane Ring,
Leading to the Synthesis of 1-Methyl-1-Alkynylcyclopropanes. J. Am.
Chem. Soc. 2009, 131, 5060−5061. See also ref 12f.
745. (e) Aïssa, C.; Furstner, A. A Rhodium-Catalyzed C−H
̈
Activation/Cycloisomerization Tandem. J. Am. Chem. Soc. 2007,
129, 14836−14837. (f) Yang, Y.; Huang, X. Intramolecular Cyclo-
isomerization of Aryl-Substituted Alkylidenecyclopropanes via NHC
Palladium-Catalyzed Cascade C−C Bond Cleavage/C−H Activation/
C−C Bond Formation. Synlett 2008, 2008, 1366−1370. (g) Cui, S.;
Zhang, Y.; Wu, Q. Rh(III)-Catalyzed C−H Activation/Cycloaddition
of Benzamides and Methylenecyclopropanes: Divergence in Ring
Formation. Chem. Sci. 2013, 4, 3421−3426. (h) Liang, Y.-F.; Mu
̈
ller,
V.; Liu, W.; Munch, A.; Stalke, D.; Ackermann, L. Methylenecyclo-
̈
propane Annulation by Manganese(I)-Catalyzed Stereoselective C−
H/C−C Activation. Angew. Chem., Int. Ed. 2017, 56, 9415−9419.
(i) Bai, D.; Xu, T.; Ma, C.; Zheng, X.; Liu, B.; Xie, F.; Li, X. Rh(III)-
Catalyzed Mild Coupling of Nitrones and Azomethine Imines with
Alkylidenecyclopropanes via C−H Activation: Facile Access to
Bridged Cycles. ACS Catal. 2018, 8, 4194−4200. (j) Dey, A.;
Thrimurtulu, N.; Volla, C. M. R. Cobalt-Catalyzed Annulation
Reactions of Alkylidenecyclopropanes: Access to Spirocyclopropanes
at Room Temperature. Org. Lett. 2019, 21, 3871−3875. (k) Li, Q.;
Yuan, X.; Li, B.; Wang, B. The Regioselective Annulation of
Alkylidenecyclopropanes by Rh(III)-Catalyzed C−H/C−C Activa-
tion to Access Spirocyclic Benzosultams. Chem. Commun. 2020, 56,
1835−1838. (l) Mo, J.; Messinis, A. M.; Oliveira, J. C. A.; Demeshko,
S.; Meyer, F.; Ackermann, L. Iron-Catalyzed Triazole-Enabled C−H
Activation with Bicyclopropylidenes. ACS Catal. 2021, 11, 1053−
1064.
(18) See the Supporting Information for more details on the
optimization of the reaction conditions.
(19) (a) Lenges, C. P.; Brookhart, M. Addition of Olefins to
Aromatic Ketones Catalyzed by Rh(I) Olefin Complexes. J. Am.
Chem. Soc. 1999, 121, 6616−6623. (b) Tsuchikama, K.; Kasagawa,
M.; Hashimoto, Y.; Endo, K.; Shibata, T. Cationic Iridium-BINAP
Complex-Catalyzed Addition of Aryl Ketones to Alkynes and Alkenes
via Directed C−H Bond Cleavage. J. Organomet. Chem. 2008, 693,
3939−3942.
(20) See the Supporting Information for details.
(21) Conservation of the cyclopropane ring is explained by the
Thorpe−Ingold effect, which suggests high thermodynamic stability
of disubstituted cyclopropanes. See also: Itazaki, M.; Nishihara, Y.;
Osakada, K. Platinum Complex-Catalyzed Hydrosilylation and
Isomerization of Methylenecyclopropane Derivatives. Effect of
Structures of the Substrate and Catalyst. J. Org. Chem. 2002, 67,
6889−6895.
(22) Although we tried to switch the homoallylation/cyclopropyl-
methylation selectivity by the reaction conditions, we could not
obtain the cyclopropylmethylation product 5 selectively. See the
Supporting Information for more details.
(23) To the best of our ability, the cyclopropylmethylation product
5 could not be isolated. See the Supporting Information for more
details on the characterization of the isomer 5 in the crude reaction
mixture.
(24) The isolated yield of 4am was decreased because it was difficult
to separate 4am from an isomer.
(25) Other directing groups such as ester, amide, imino, and pyridyl
groups were examined but failed to give the homoallylation products.
See the Supporting Information for more details on the unsuccessful
substrates.
(26) For more information about 1,2-dihydronaphthalenes, see:
(a) Li, X.; Wang, S.; Li, T.; Li, J.; Li, H.; Wang, W. Formation of
Dihydronaphthalenes via Organocatalytic Enatioselective Michael−
Aldol Cascade Reactions with Arylalkanes. Org. Lett. 2013, 15, 5634−
5637. (b) te Grotenhuis, C.; Das, B. G.; Kuijpers, P. F.; Hageman, W.;
Trouwborst, M.; de Bruin, B. Catalytic 1,2-Dihydronaphthalene and
E-Aryl-diene Synthesis via CoIII−Carbene Radical and o-Quinodi-
methane Intermediates. Chem. Sci. 2017, 8, 8221−8230.
(27) (a) Fu, G. C.; Grubbs, R. H. Synthesis of Cycloalkenes via
Alkylidene-Mediated Olefin Metathesis and Carbonyl Olefination. J.
Am. Chem. Soc. 1993, 115, 3800−3801. (b) Heller, S. T.; Kiho, T.;
Narayan, A. R. H.; Sarpong, R. Protic-Solvent-Mediated Cyclo-
isomerization of Quinoline and Isoquinoline Propargylic Alcohols:
Syntheses of ( )-3-Demethoxyerythratidinone and ( )-Cocculidine.
Angew. Chem., Int. Ed. 2013, 52, 11129−11133. (c) Hong, B.; Li, H.;
Wu, J.; Zhang, J.; Lei, X. Total Syntheses of (−)-Huperzine Q and
(+)-Lycopladines B and C. Angew. Chem., Int. Ed. 2015, 54, 1011−
1015.
(13) (a) Li, M.; Kwong, F. Y. Cobalt-Catalyzed Tandem C−H
Activation/C−C Cleavage/C−H Cyclization of Aromatic Amides
with Alkylidenecyclopropanes. Angew. Chem., Int. Ed. 2018, 57,
6512−6516. (b) Zhu, Y.-Q.; Niu, Y.-X.; Hui, L.-W.; He, J.-L.; Zhu, K.
Reaction of Isoquinolin-1(2H)-Ones with Methylenecyclopropanes
via Rhodium(III)-Catalyzed C−H Activation. Adv. Synth. Catal. 2019,
361, 2897−2903. (c) Liu, R.; Wei, Y.; Shi, M. A Rhodium(III)-
Catalyzed Tunable Coupling Reaction of Indole Derivatives with
Alkylidenecyclopropanes via C−H Activation. Chem. Commun. 2019,
55, 7558−7561.
(14) For selected synthesis of ortho-homoallylated aromatic ketones,
see: (a) Lin, S.; Song, C.-X.; Cai, G.-X.; Wang, W.-H.; Shi, Z.-J. Intra/
Intermolecular Direct Allylic Alkylation via Pd(II)-Catalyzed Allylic
C−H Activation. J. Am. Chem. Soc. 2008, 130, 12901−12903.
(b) Soicke, A.; Slavov, N.; Neudörfl, J.-M.; Schmalz, H.-G. Metal-Free
Intramolecular Carbonyl-Olefin Metathesis of ortho-Prenylaryl
Ketones. Synlett 2011, 2011, 2487−2490. (c) Masuda, Y.; Makita,
K.; Murakami, M. Dehydrative Allylation of 2-Alkylbenzophenones
with Allylic Alcohols. Chem. Lett. 2020, 49, 616−618.
(15) (a) Kimura, N.; Kochi, T.; Kakiuchi, F. Iron-Catalyzed
Regioselective Anti-Markovnikov Addition of C−H Bonds in
Aromatic Ketones to Alkenes. J. Am. Chem. Soc. 2017, 139, 14849−
14852. (b) Kimura, N.; Kochi, T.; Kakiuchi, F. Iron-Catalyzed Ortho-
Selective C−H Alkylation of Aromatic Ketones with N-Alkenylindoles
and Partial Indolylation via 1,4-Iron Migration. Asian J. Org. Chem.
2019, 8, 1115−1117.
(16) Messinis, A. M.; Finger, L. H.; Hu, L.; Ackermann, L. Allenes
for Versatile Iron-Catalyzed C−H Activation by Weak O-Coordina-
tion: Mechanistic Insights by Kinetics, Intermediate Isolation, and
Computation. J. Am. Chem. Soc. 2020, 142, 13102−13111.
(17) In the reaction of ruthenium-catalyzed C−H cyclopropylme-
thylation (ref 11a−11c), the homoallylation products were not
obtained because β-hydride elimination of homoallylruthenium
intermediates into ruthenium hydrides and 1,3-dienes is faster than
reductive elimination. On the other hand, 1,3-dienes were not
detected in this iron-catalyzed reaction. Based on these results, β-
hydride elimination of homoallyliron intermediates may be slow, thus
providing the homoallylation products via reductive elimination.
(28) See the Supporting Information for more details.
(29) Direct involvement of Ackermann’s intermediate having three
trimethylphosphines,16 formed by oxidative addition of the aromatic
4548
https://doi.org/10.1021/jacs.1c00237
J. Am. Chem. Soc. 2021, 143, 4543−4549

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
ketone, in the catalytic cycle is less likely for the reaction with MCPs.
See the Supporting Information for more details.
(30) (a) Foerstner, J.; Kozhushkov, S.; Binger, P.; Wedemann, P.;
Noltemeyer, M.; de Meijere, A.; Butenschön, H. The First Metal
Complexes of Bicyclopropylidene, a Unique Tetrasubstituted Alkene
Ligand. Chem. Commun. 1998, 239−240. (b) Kozhushkov, S. I.;
Foerstner, J.; Kakoschke, A.; Stellfeldt, D.; Yong, L.; Wartchow, R.; de
Meijere, A.; Butenschön, H. Syntheses and Structures of Sterically
Congested Linear and Branched Cobalta[n]triangulanes. Chem. - Eur.
J. 2006, 12, 5642−5647. (c) Hoyte, S. A.; Spencer, J. L. Mono- and
Diphosphine Platinum(0) Complexes of Methylenecyclopropane,
Bicyclopropylidene, and Allylidenecyclopropane. Organometallics
2011, 30, 5415−5423.
(31) Chirik, P. J.; Bercaw, J. E. Cyclopentadienyl and Olefin
Substituent Effects on Insertion and β-Hydrogen Elimination with
Group 4 Metallocenes. Kinetics, Mechanism, and Thermodynamics
for Zirconocene and Hafnocene Alkyl Hydride Derivatives. Organo-
metallics 2005, 24, 5407−5423.
4549
https://doi.org/10.1021/jacs.1c00237
J. Am. Chem. Soc. 2021, 143, 4543−4549