Palladium-Catalyzed Defluorinative Alkylation of gem-Difluorocyclopropanes: Switching Regioselectivity via Simple Hydrazones

Article abstract of DOI:10.1002/anie.202102240

Conventional approaches for Pd-catalyzed ring-opening cross-couplings of gem-difluorocyclopropanes with nucleophiles predominantly deliver the β-fluoroalkene scaffolds (linear selectivity). Herein, we report a cooperative strategy that can completely switch the reaction selectivity to give the alkylated α-fluoroalkene skeletons (branched selectivity). The unique reactivity of hydrazones that enables analogous inner-sphere 3,3′-reductive elimination driven by denitrogenation, as well as the assistance of steric-embedded N-heterocyclic carbene ligand, are the key to switch the regioselectivity. A wide range of hydrazones derived from naturally abundant aryl and alkyl aldehydes are well applicable, and various gem-difluorocyclopropanes, including modified pharmaceutical and biological molecules, can be efficiently functionalized with high value alkylated α-fluorinated alkene motifs under mild conditions.

Full text of DOI:10.1002/anie.202102240

Angewandte
Research Articles
Chemie
How to cite:
International Edition: doi.org/10.1002/anie.202102240
German Edition: doi.org/10.1002/ange.202102240
Synthetic Methods
Palladium-Catalyzed Defluorinative Alkylation of gem-
Difluorocyclopropanes: Switching Regioselectivity via Simple
Hydrazones
Leiyang Lv* and Chao-Jun Li*
Abstract: Conventional approaches for Pd-catalyzed ring-
opening cross-couplings of gem-difluorocyclopropanes with
nucleophiles predominantly deliver the b-fluoroalkene scaf-
folds (linear selectivity). Herein, we report a cooperative
strategy that can completely switch the reaction selectivity to
give the alkylated a-fluoroalkene skeletons (branched selec-
tivity). The unique reactivity of hydrazones that enables
analogous inner-sphere 3,3’-reductive elimination driven by
denitrogenation, as well as the assistance of steric-embedded N-
heterocyclic carbene ligand, are the key to switch the regiose-
lectivity. A wide range of hydrazones derived from naturally
abundant aryl and alkyl aldehydes are well applicable, and
various gem-difluorocyclopropanes, including modified phar-
maceutical and biological molecules, can be efficiently func-
tionalized with high value alkylated a-fluorinated alkene
motifs under mild conditions.
value mono-fluorinated alkene structures in a well-defined
manner remains highly desirable.
Gem-difluorocyclopropanes are readily available (easily
prepared from simple alkenes and difluorocarbene precur-
À
sors), structurally unique (the C C bond being highly
polarized) and versatile fluoroalkylating reagents.[6] By taking
advantage of transition-metal-catalyzed ring-opening strat-
egy, Fu and co-workers[7] reported the first Pd-catalyzed C C
À
activation/C F cleavage[8] of gem-difluorocyclopropanes with
À
various nucleophiles (N, O) to construct mono-fluorinated
alkene skeletons with high regioselectivity (linear product)
and stereoselectivity (Z-configuration) (Scheme 1a). This
strategy was further extended to prepare an array of appeal-
À
À
ing b-fluoroalkene structures integrated with C C, C N or
[9]
À
C S bond formations. Very recently, Xia and co-workers
À
reported an elegant Rh-catalyzed C H allylation of arenes
with gem-difluorocyclopropanes.[10] Mechanistically, those
external nucleophiles (whether interact with the metal center
or not) preferentially attack at the sterically less hindered C1
atom, and the linear fluorinated allylic scaffolds (b-fluoroal-
Introduction
The introduction of fluorine atoms or fluorine-containing
scaffolds into molecules can provide unique chemical or
physical properties and significant improvement in their
biological and pharmacological activities, which has been
widely utilized in medicinal chemistry and drug-discovery
research.[1,2] In this context, mono-fluoroalkenes have been
drawing increasing interest, owing to their potential use as
amide bond isosteres or mimics of enols, as well as their far-
reaching applications in materials science and synthetic
organic chemistry.[3] Typical protocols for the preparation of
mono-fluoroalkenes include addition,[4a] olefination,[4b] elim-
ination,[4c] and transition-metal-catalyzed cross-coupling re-
actions.[4d–f] Although many efforts have been made in this
field,[5] several problems such as precise control of the regio-
and stereo-selectivity and functional group compatibility still
exist. Therefore, the general and practical synthesis of high
[*] Prof. L. Lv
Department of Chemistry, Renmin University of China
Beijing 100872 (China)
E-mail: lvleiyang2008@ruc.edu.cn
Prof. C.-J. Li
Department of Chemistry and FRQNT Center for Green Chemistry
and Catalysis, McGill University
801 Sherbrooke Street West, Montreal, Quebec H3A 0B8 (Canada)
E-mail: cj.li@mcgill.ca
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202102240.
Scheme 1. Functionalization of gem-difluorocyclopropanes to synthe-
size mono-fluorinated alkene scaffolds and the strategy to switch the
regioselectivity.
&&&&
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 2 – 9
These are not the final page numbers!

Angewandte
Research Articles
Chemie
kenes) were obtained predominantly (Scheme 1c, left) via the
p-coordination.
As is well-known, rationally manipulating reaction selec-
tivity for regio-divergent synthesis by utilizing and/or over-
coming the intrinsic electronic and steric bias is a perpetual
subject for chemists.[11] In view of the privileged significance
of a-fluoroalkene motifs in drugs, agrochemicals and materi-
als, we wondered if we could overcome the innate reactivity to
gain high level of branch-enriched fluorinated allylic skele-
tons also from the same gem-difluorocyclopropane precursors
via the s-coordination.
Inspired by Echavarren[12] and Morkenꢀs elegant works[13]
on the regio-controlled allyl-allyl cross-couplings via 3,3’-
reductive elimination pathway (Scheme 1b), and combined
with our expertise on hydrazones acting as alkyl carboanion
equivalents in the nucleophilic additions[14] and cross-coupling
reactions,[15] we hypothesized that gem-difluorocyclopropane
could be used as allyl electrophile with simple hydrazone as
diazaallyl partner.[16] The readily formed putative allyl,
diazaallyl-palladium intermediate would allow for the anal-
ogous inner-sphere 3,3’-reductive elimination, thus ensuring
the nucleophiles to attack at the sterically more hindered C3
atom (Scheme 1c, right). Besides, based on the literature[17]
and our previous work on Pd-catalyzed hydroalkylation of
methylenecyclopropanes with hydrazones as pronucleo-
philes,[15e] we also reasoned that a subsequent denitrogenation
activity might take place, which in turn would accelerate the
3,3’-reductive elimination process cooperatively. Assuming
that our proposal is viable, there comes with an affiliated
benefit that alkyl groups could be incorporated into the
monofluoroalkene scaffolds, which is potentially complemen-
tary to the Au-catalyzed hydrofluorination reaction of
terminal alkyne.[4a] With this design in mind, herein we wish
to report that a switched regioselectivity of Pd-catalyzed
defluorination alkylation of gem-difluorocyclopropanes was
enabled by simple hydrazones, and the branch-enriched
monofluorinated alkene products were obtained selectively
(Scheme 1d).
Scheme 2. Possible intermediates encountered in the allyl-(diaza)allyl
cross-couplings.
cross-coupling, the ambident nucleophilic sites (C-terminal
and N-terminal)[20] in hydrazone part may result in additional
bis(h1-allyl) bonding modes (V, VI and VII), which are
detrimental to the designed regioselectivity. Last but not the
least, different from allyl-allyl cross-coupling, an appended
denitrogenative event is expected to complete the ring
opening-alkylation process.
With these concerns in mind, a palladium/bidentate
phosphine system was initially adopted to start our study
with the model reaction of 2-(2,2-difluorocyclopropyl)naph-
thalene (1a) and phenyl hydrazone (2a) (Table 1). However,
no expected product 3a was obtained with small bite-angle
bidentate phosphine ligand, which indicated that the allyl-
(diaza)allyl cross-coupling might be quite different from the
previous allyl-allyl one. We then reanalyzed the possible
intermediates (V–VIII) in Scheme 2 and envisioned that in
order to make the least hindered bis(h1-allyl) species VIII
favorable, the steric-embedded coordination ligand might be
beneficial due to its repulsion to the substituents (R or R1).
Therefore, a series of bulky ligands, such as PCy3, PtBu3,
RuPhos, Xphos and NHCs (N-heterocyclic carbenes) were
examined accordingly (entries 1–8). We were pleased to find
that the anticipated branched fluoroalkene product 3a could
be selectively obtained in 97% yield when the carbene ligand
precursor SIPr·HCl [1,3-bis(2,6-diisopropylphenyl)imidazoli-
um chloride] was used in presence of KOH in THFat 458C for
12 h (entry 8). In order to simplify the experimental proce-
dure, the air-stable and commercially-available Pd-PEPPSI-
SIPr catalyst was employed and 3a was afforded in compa-
rable yield and regioselectivity (entry 9). Base was utilized to
mediate the hydrazone deprotonation, and its choice was also
crucial to facilitate the final denitrogenation. No desired
product was observed when strong bases such as KOtBu and
LiOtBu were tested, owing to the dominant Wolff–Kishner
reduction of hydrazone (entries 10 and 11). Organic base
DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) did not work for
the defluorination alkylation reaction (entry 12). Relatively
Results and Discussion
To realize this hypothesis, several challenges must be
taken into consideration (Scheme 2). Firstly, to make the
reaction operate via a 3,3’-reductive elimination, the coordi-
nation ligand must play a key role, which should render both
(aza)allyl groups to adopt h1-bonding mode (II or III) other
than the more common h3-bonding mode (I). Secondly, two
kinds of bis(h1-allyl) bonding modes are available when the
substitution (R) is present, and the sterically less hindered
bis(h1-allyl) species (III) is supposed be predominant to favor
3,3’-reductive elimination (the direct elimination from inter-
mediate II is less likely[18]) relative to the 1,1’-path. As
revealed by Morkenꢀs work,[19] small-bite-angle bidentate
phosphine ligands could effectively increase both the C1-C1’
separation and promote the formation of desired bis(h1-allyl)
bonding mode. Whether it also works or not in our system, the
general principle to choose appropriate ligands is well
applicable. Thirdly, considering the analogous allyl-diazaallyl
Angew. Chem. Int. Ed. 2021, 60, 2 – 9
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org
&&&&
These are not the final page numbers!

Angewandte
Research Articles
Chemie
Table 1: Optimization of the reaction conditions.[a]
afford the branched monofluoroalkene products 3b–n in 84–
95% yields. The reaction efficiency was almost not hampered
even with the sterically bulky hydrazone that prepared from
mesitaldehyde (3e, 87%). Various functional groups, for
example, methoxy (3g), methylenedioxy (3h), methylthio
(3i), trifluoromethoxy (3j), fluoro (3k, 3l) and trifluorometh-
yl (3m), were well tolerated under the optimized conditions.
In the presence of sensitive ester group, a slightly modified
reaction conditions (Cs2CO3 used instead of KOH) was
employed to maintain the efficient reactivity (3n, 84%).
Hydrazones that prepared from polycyclic aromatic alde-
hydes such as 1-naphthaldehyde and 2-naphthaldehyde were
also suitable substrates (3o, 3p). Notably, heterocyclic-con-
taining hydrazones including furan, pyrrole and carbazole
also reacted smoothly, delivering the desired products 3q–s in
82–95% yields. Due to the lack of stabilization from the
aromatic ring, hydrazones that derived from aliphatic alde-
hydes were typically unreactive or less efficient in most of the
previously reported cross-coupling reactions. To our delight,
this drawback was successfully overcome with the Pd/NHC
catalytic system, and the desired alkylated monofluoroalkene
products 3t–y were obtained in 85–92% yields (Table 2b).
Moreover, aliphatic hydrazones bearing ether, protected
alcohol (-OTBS) or amines (-NBoc, -NCbz) could also
deliver the desired products 3z–3ac in moderate to excellent
yields. To this end, hydrazones behaved as not only the limited
benzylation reagents but also the more general alkylation
reaction partners.
Entry [Pd]
L
Base
Yield[b]
3a [%]
3a/3a’[c]
1
2
3
4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PCy3
KOH
KOH
KOH
KOH
KOH
N.D.
N.D.
34
–
–
3:1
60:1
–
–
33:1
80:1
PtBu3
XPhos
Ruphos
IMes·HCl
42
5
Pd(OAc)2
trace
trace
91
6
Pd(OAc)2
SIMes·HCl KOH
7
Pd(OAc)2
IPr·HCl
KOH
8
Pd(OAc)2
SIPr·HCl
KOH
97
9[d]
10
11
12
13
14
15
16
Pd-PEPPSI-SIPr
Pd-PEPPSI-SIPr
Pd-PEPPSI-SIPr
Pd-PEPPSI-SIPr
Pd-PEPPSI-SIPr
Pd-PEPPSI-SIPr
–
–
–
–
–
–
–
KOH
97 (94) 80:1
KOtBu
LiOtBu
DBU
N.D.
N.D.
N.D.
73
–
–
–
K3PO4
Cs2CO3 91
KOH
KOH
18:1
27:1
–
SIPr·HCl
–
N.D.
N.D.
Pd(OAc)2
–
Next, we surveyed the substrate scope with respect to
gem-difluorocyclopropanes (Table 2c). It was found that
diverse electronic or steric biased substituents attached to
the gem-difluorocyclopropanes were well accommodated
under the standard conditions. Both electron-donating groups
such as methyl (4b), tert-butyl (4c), methoxy (4e) and
benzyloxy (4 f) as well as the electron withdrawing groups
such as fluoro (4g), ester (4h) and tosyl (4i) on the arene rings
were tolerated, affording the corresponding products in 86–
96% yields. The 2,5-dimethyl substituted difluorocyclopropyl
benzene also gave the expected product 4d in 94% yield. The
chloro substituent on the arene (4j) could not survive due to
its facile interaction with palladium catalyst. Reaction with
gem-difluorinated cyclopropane that derived from but-3-en-
1-ylbenzene (4k) was also successful. When the gem-difluori-
nated substrate prepared from 1-vinylpyrrolidin-2-one was
tested under optimal conditions, the branched product 4l was
generated exclusively in a 32% yield, possibly due to
deactivation of the metal catalyst by the coordination of
amide group.[17] It should be noted that this transformation
was observed to be quite sensitive to the steric bias on the
cyclopropane part. For example, only gem-difluorinated
cyclopropanes with one substituent at the terminal position
(e.g., those derived from mono-substituted alkenes with
difluorocarbene precursors) were viable substrates, whereas
gem-disubstituted difluorocyclopropanes as well as the inter-
nal ones were not applicable with this protocol.
[a] Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), palladium
catalyst (5.0 mol%), ligand (5.0 mol%), base (0.2 mmol), THF (1.0 mL),
458C, 12 h under N2 unless otherwise noted. [b] NMR yields were based
1
on 1a and determined by H NMR spectroscopy using CH2Br2 as an
internal standard. [c] The 3a/3a’ ratio was determined by 1H NMR
analysis of the crude mixtures. [d] Isolated yield in parenthesis.
N.D.=not detected.
weak bases such as K3PO4 and Cs2CO3 could deliver the
product 3a in good yields yet with diminished regioselectivity
(entries 13 and 14). One explanation may be that the slower
deprotonation of hydrazone resulted in the shift of its
coordination site with palladium to the C-terminal. Control
experiments revealed that no desired product 3a was
obtained in the absence of either the palladium catalyst or
a ligand (entries 15 and 16).
With an effective tactic to control the regioselectivity in
allyl-diazaallyl cross-coupling reactions in hand, the substrate
scope with respect to various easily available hydrazones and
gem-difluorocyclopropanes was investigated, and the results
were shown in Table 2. An array of simple hydrazones
(derived from naturally abundant aryl and alkyl aldehydes)
bearing either electron-donating or electron-withdrawing
groups regardless of the para-, meta- or ortho-substitutions
on the aromatic rings, were all competent reaction partners to
To further exemplify the value of this palladium-catalyzed
regioselective defluoroalkylation protocol, the biologically
and pharmaceutically related substrates were evaluated. As
shown in Table 2d, a series of bioactive molecules assembled
&&&&
www.angewandte.org
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 2 – 9
These are not the final page numbers!

Angewandte
Research Articles
Chemie
Table 2: Scope of substrates.[a]
[a] Reaction conditions: 1 (0.1 mmol), 2 (0.2 mmol), Pd-PEPPSI-SIPr (5.0 mol%), KOH (0.2 mmol), THF (1.0 mL), 458C, 12 h under N2. Reported
yields are the ones of the isolated products, the branched:linear ratio was more than 20:1 unless otherwise noted. [b] Cs2CO3 was used instead of
KOH. [c] 608C. [d] The yield in parenthesis was calculated based on recovered starting material. [e] The diastereoselectivity in parentheses was
1
determined by H NMR analysis of the crude mixtures. PG=protecting group.
Angew. Chem. Int. Ed. 2021, 60, 2 – 9
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org
&&&&
These are not the final page numbers!

Angewandte
Research Articles
Chemie
with the a-fluoroalkene motif, including estrone derivative
(4m), diacetone-D-glucose derivative (4n), naproxen deriv-
ative (4o) as well as a-tocopherol derivative (4p), were
obtained with this method in good yields (> 80%) with 1:1
diastereoisomers. These examples highlighted the broad
applicability and compatibility of the current approach,
meanwhile enriched the toolbox of chemists for the equip-
ment of bioactive molecules with a-fluoroalkene scaffolds.
Notwithstanding, the lack of stereo-control is the limitation of
the reaction at this stage.
To gain preliminary insight into the reaction mechanism,
several control and deuterium experiments were then carried
out (Scheme 3). When N-tosylhydrazone 5, commonly uti-
lized as the carbene precursor, was tested instead of
hydrazone to react with 1a under the standard conditions,
no desired product 3a was detected. This outcome indicated
the unlikely involvement of a carbene process in this trans-
formation [Scheme 3, Eq. (a)]. When the reaction was carried
out in the presence of radical inhibitors such as butylated
hydroxytoluene (BHT) or 1,1-diphenylethylene, the yield of
3a was not affected, which precluded the possibility of
a radical mechanism [Scheme 3, Eqs. (b) and (c)]. Deuterium-
labeling experiment with 2a-d2 (66%) showed that deuterium
were exclusively incorporated into the benzyl position in 3a-
d1, which suggested that hydrazone served as both the alkyl
nucleophile and hydrogen donor [Scheme 3, Eq. (d)]. When
deuterated hydrazone 2p-d1 was conducted with 1a under
optimal conditions, the aldehydic hydrogen was preserved
completely in 3p-d1 and no observation of H/D scrambling
between benzylic and other moiety. This result revealed that
À
there were no C H activation of hydrazone or generation of
Pd-H species during this transformation [Scheme 3, Eq. (e)].
Besides, to explore the practicality of this defluorination
alkylation method, the reaction of 2-(2,2-difluorocyclopro-
pyl)naphthalene (1a) with phenyl hydrazone (2a) was carried
out in gram-scale. Gratifyingly, the desired product 3a was
obtained in excellent yield (93%, 1.03 g) even with a reduced
palladium loading (2.0 mol%) [Scheme 3, Eq. (f)].
Based on these results and our previous work, a plausible
reaction mechanism is proposed (Scheme 4). Initially, oxida-
À
tive addition of the strained C C bond in 1 gives the
intermediate A, upon which b-F elimination occurs to afford
the 2-fluorinated palladium p-allyl complex B. Then trans-
metallation of B with amphipathic nucleophile that derived
from deprotonated hydrazone 2 delivers the key sterically less
hindered bis(h1-allyl) species C, which undergoes regioselec-
tive 3,3’-reductive elimination to afford the intermediate D
and regenerate Pd catalyst. Finally, decomposition of D via
deprotonation and N2 extrusion releases the desired product 3
or 4.
Scheme 4. Proposed reaction mechanism.
Conclusion
In summary, we have developed a highly effective and
regioselective Pd-catalyzed defluorinative alkylation of gem-
difluorocyclopropanes with simple hydrazones. This reaction
proceeds smoothly under mild reaction conditions to deliver
a series of high value a-fluorinated alkene scaffolds compli-
mentary to the previously documented b-fluorinated ones in
good to excellent yields. The unique trifunctional reactivity of
hydrazones is crucial for the success of this transformation
and can be ascribed as follows: 1) assisting inner-sphere 3,3’-
reductive elimination via forming putatively allyl, diazaallyl-
Scheme 3. Control and deuterium experiments and gram-scale syn-
thesis.
&&&&
www.angewandte.org
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 2 – 9
These are not the final page numbers!

Angewandte
Research Articles
Chemie
[4] a) O. E. Okoromoba, J. Han, G. B. Hammond, B. Xu, J. Am.
palladium complex; 2) accelerating the reductive elimination
process through loss of nitrogen gas; 3) acting as alkylating
reagents. Moreover, the cooperation of palladium with steri-
cally hindered NHC ligand is also indispensable to ensure the
switched regioselectivity. Last but not the least, this protocol
displays great compatibility with various functional groups,
thus providing a straightforward access to incorporate a-
fluoroalkene unit into pharmaceutically relevant molecules
that may be useful in drug discovery. Further studies to
elucidate the mechanism and asymmetric synthesis are on-
going in our lab.
Chem. Soc. 2014, 136, 14381 – 14384; b) Q. Liu, X. Shen, C. Ni, J.
Hu, Angew. Chem. Int. Ed. 2017, 56, 619 – 623; Angew. Chem.
2017, 129, 634 – 638; c) J. Hu, X. Han, Y. Yuan, Z. Shi, Angew.
Chem. Int. Ed. 2017, 56, 13342 – 13346; Angew. Chem. 2017, 129,
13527 – 13531; d) P. Tian, C. Feng, T.-P. Loh, Nat. Commun. 2015,
6, 7472; e) R. T. Thornbury, F. D. Toste, Angew. Chem. Int. Ed.
2016, 55, 11629 – 11632; Angew. Chem. 2016, 128, 11801 – 11804;
f) X. Lu, Y. Wang, B. Zhang, J.-J. Pi, X.-X. Wang, T.-J. Gong, B.
Xiao, Y. Fu, J. Am. Chem. Soc. 2017, 139, 12632 – 12637.
[5] a) B. Zajc, R. Kumar, Synthesis 2010, 1822 – 1836; b) E. Pfund, T.
Lequeux, D. Gueyrard, Synthesis 2015, 47, 1534 – 1546; c) J. H.
van Steenis, A. van der Gen, J. Chem. Soc. Perkin Trans. 1 2002,
2117 – 2133; d) H. Yanai, T. Taguchi, Eur. J. Org. Chem. 2011,
5939 – 5954; e) S. Hara, Top. Curr. Chem. 2012, 327, 59; f) M.
Drouin, J.-D. Hamel, J.-F. Paquin, Synthesis 2018, 50, 881 – 955.
[6] a) W. R. Dolbier, M. A. Battiste, Chem. Rev. 2003, 103, 1071 –
1098; b) F. Wang, T. Luo, J. Hu, Y. Wang, H. S. Krishnan, P. V.
Jog, S. K. Ganesh, G. K. S. Prakash, G. A. Olah, Angew. Chem.
Int. Ed. 2011, 50, 7153 – 7157; Angew. Chem. 2011, 123, 7291 –
Acknowledgements
We thank the support by the Canada Research Chair
Foundation (to C.-J.L.), the Canadian Foundation for Inno-
vation, FRQNT Centre in Green Chemistry and Catalysis,
and the Natural Science and Engineering Research Council of
Canada and the Killam Research Fellow of the Canadian
Council of Arts. The research is also supported by the
Fundamental Research Funds (to L.L.) for the Central
Universities, the Research Funds of Renmin University of
China (21XNLG04, 21XNH087).
´
7295; c) M. Fedorynski, Chem. Rev. 2003, 103, 1099 – 1132.
[7] J. Xu, E.-A. Ahmed, B. Xiao, Q.-Q. Lu, Y.-L. Wang, C.-G. Yu, Y.
Fu, Angew. Chem. Int. Ed. 2015, 54, 8231 – 8235; Angew. Chem.
2015, 127, 8349 – 8353.
[8] a) H. Amii, K. Uneyama, Chem. Rev. 2009, 109, 2119 – 2183;
b) T. Fujita, K. Fuchibe, J. Ichikawa, Angew. Chem. Int. Ed. 2019,
58, 390 – 402; Angew. Chem. 2019, 131, 396 – 408.
[9] a) E.-A. M. A. Ahmed, A. M. Y. Suliman, T.-J. Gong, Y. Fu,
Org. Lett. 2019, 21, 5645 – 5649; b) J. Ni, B. Nishonov, A.
Pardaev, A. Zhang, J. Org. Chem. 2019, 84, 13646 – 13654; c) E.-
A. M. A. Ahmed, A. M. Y. Suliman, T.-J. Gong, Y. Fu, Org. Lett.
2020, 22, 1414 – 1419.
[10] Z.-T. Jiang, J. Huang, Y. Zeng, F. Hu, Y. Xia, Angew. Chem. Int.
Ed. 2021, https://doi.org/10.1002/anie.202016258; Angew. Chem.
2021, https://doi.org/10.1002/ange.202016258.
[11] a) B. M. Trost, Science 1983, 219, 245 – 250; b) J. Mahatthanan-
chai, A. M. Dumas, J. W. Bode, Angew. Chem. Int. Ed. 2012, 51,
10954 – 10990; Angew. Chem. 2012, 124, 11114 – 11152.
[12] M. Mꢅndez, J. M. Cuerva, E. Gꢁmez-Bengoa, D. J. Cꢂrdenas,
A. M. Echavarren, Chem. Eur. J. 2002, 8, 3620 – 3628.
[13] a) P. Zhang, L. A. Brozek, J. P. Morken, J. Am. Chem. Soc. 2010,
132, 10686 – 10688; b) L. A. Brozek, M. J. Ardolino, J. P. Mork-
en, J. Am. Chem. Soc. 2011, 133, 16778 – 16781.
[14] a) H. Wang, X.-J. Dai, C.-J. Li, Nat. Chem. 2017, 9, 374 – 378;
b) N. Chen, X.-J. Dai, H. Wang, C.-J. Li, Angew. Chem. Int. Ed.
2017, 56, 6260 – 6263; Angew. Chem. 2017, 129, 6356 – 6359;
c) X.-J. Dai, H. Wang, C.-J. Li, Angew. Chem. Int. Ed. 2017, 56,
6302 – 6306; Angew. Chem. 2017, 129, 6399 – 6403.
[15] a) D. Zhu, L. Lv, C. C. Li, S. Ung, J. Gao, C.-J. Li, Angew. Chem.
Int. Ed. 2018, 57, 16520 – 16524; Angew. Chem. 2018, 130, 16758 –
16762; b) L. Lv, D. Zhu, J. Tang, Z. Qiu, C. C. Li, J. Gao, C.-J. Li,
ACS Catal. 2018, 8, 4622 – 4627; c) L. Lv, L. Yu, Z. Qiu, C.-J. Li,
Angew. Chem. Int. Ed. 2020, 59, 6466 – 6472; Angew. Chem.
2020, 132, 6528 – 6534; d) L. Lv, D. Zhu, C.-J. Li, Nat. Commun.
2019, 10, 715; e) J. Yao, Z. Chen, L. Yu, L. Lv, D. Cao, C.-J. Li,
Chem. Sci. 2020, 11, 10759 – 10763. For an account, see: f) C.-J.
Li, J. Huang, X.-J. Dai, H. Wang, N. Chen, W. Wei, H. Zeng, J.
Tang, C. Li, D. Zhu, L. Lv, Synlett 2019, 30, 1508 – 1524.
[16] a) S. Breitler, E. M. Carreira, J. Am. Chem. Soc. 2015, 137, 5296 –
5299; b) I. Westmoreland, I. J. Munslow, A. J. Clarke, G.
Clarkson, P. Scott, Organometallics 2004, 23, 5066 – 5074;
c) E. H. El Mamouni, M. Cattoen, M. Cordier, J. Cossy, S.
Arseniyadis, H. Ilitki, L. El Kaꢆm, Chem. Commun. 2016, 52,
14490 – 14493.
Conflict of interest
The authors declare no conflict of interest.
Keywords: alkylation · defluorination · fluoroalkenes ·
gem-difluorocyclopropane · hydrazones
[1] a) J. Moschner, V. Stulberg, R. Fernandes, S. Huhmann, J.
Leppkes, B. Koksch, Chem. Rev. 2019, 119, 10718 – 10801; b) R.
Szpera, D. F. J. Moseley, L. B. Smith, A. J. Sterling, V. Gouver-
neur, Angew. Chem. Int. Ed. 2019, 58, 14824 – 14848; Angew.
Chem. 2019, 131, 14966 – 14991; c) N. A. Meanwell, J. Med.
Chem. 2018, 61, 5822 – 5880; d) Y. Zhu, J. Han, J. Wang, N.
Shibata, M. Sodeoka, V. A. Soloshonok, J. A. S. Coelho, F. D.
Toste, Chem. Rev. 2018, 118, 3887 – 3964; e) J. Mirꢁ, C. del Pozo,
Chem. Rev. 2016, 116, 11924 – 11966; f) J. Wang, M. Sꢂnchez-
Rosellꢁ, J. L. AceÇa, C. del Pozo, A. E. Sorochinsky, S. Fustero,
V. A. Soloshonok, H. Liu, Chem. Rev. 2014, 114, 2432 – 2506;
g) T. Liang, C. N. Neumann, T. Ritter, Angew. Chem. Int. Ed.
2013, 52, 8214 – 8264; Angew. Chem. 2013, 125, 8372 – 8423; h) S.
Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev.
2008, 37, 320 – 330.
[2] a) K. Mꢃller, C. Faeh, F. Diederich, Science 2007, 317, 1881; b) T.
Furuya, A. S. Kamlet, T. Ritter, Nature 2011, 473, 470 – 477; c) J.
Charpentier, N. Frꢃh, A. Togni, Chem. Rev. 2015, 115, 650 – 682;
d) Q. Liu, C. Ni, J. Hu, Natl. Sci. Rev. 2017, 4, 303 – 325.
[3] a) S. Osada, S. Sano, M. Ueyama, Y. Chuman, H. Kodama, K.
Sakaguchi, Bioorg. Med. Chem. 2010, 18, 605 – 611; b) S. Couve-
Bonnaire, D. Cahard, X. Pannecoucke, Org. Biomol. Chem.
2007, 5, 1151 – 1157; c) P. Van der Veken, K. Senten, I. Kertꢄsz, I.
De Meester, A.-M. Lambeir, M.-B. Maes, S. Scharpꢅ, A.
Haemers, K. Augustyns, J. Med. Chem. 2005, 48, 1768 – 1780;
d) P. A. Champagne, J. Desroches, J.-D. Hamel, M. Vandamme,
J.-F. Paquin, Chem. Rev. 2015, 115, 9073 – 9174; e) G. Landelle,
M. Bergeron, M.-O. Turcotte-Savard, J.-F. Paquin, Chem. Soc.
Rev. 2011, 40, 2867 – 2908.
[17] A. Takemiya, J. F. Hartwig, J. Am. Chem. Soc. 2006, 128, 14800 –
14801.
Angew. Chem. Int. Ed. 2021, 60, 2 – 9
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org
&&&&
These are not the final page numbers!

Angewandte
Research Articles
Chemie
[18] H. Nakamura, K. Aoyagi, J.-G. Shim, Y. Yamamoto, J. Am.
Chem. Soc. 2001, 123, 372 – 377.
J. F. Hartwig, Angew. Chem. Int. Ed. 2007, 46, 7259 – 7261;
Angew. Chem. 2007, 119, 7397 – 7399.
[19] M. J. Ardolino, J. P. Morken, J. Am. Chem. Soc. 2014, 136, 7092 –
7100.
[20] a) S. Tang, X. Zhang, J. Sun, D. Niu, J. J. Chruma, Chem. Rev.
2018, 118, 10393 – 10457; b) B. Lu, B. Feng, H. Ye, J.-R. Chen, W.-
J. Xiao, Org. Lett. 2018, 20, 3473 – 3476; c) A. M. Johns, Z. Liu,
Manuscript received: February 12, 2021
Revised manuscript received: March 12, 2021
Accepted manuscript online: March 23, 2021
Version of record online: && &&
,
&&&&
&&&&
www.angewandte.org
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 2 – 9
These are not the final page numbers!

Angewandte
Research Articles
Chemie
Research Articles
Synthetic Methods
L. Lv,* C.-J. Li*
&&&& — &&&&
Palladium-Catalyzed Defluorinative
Alkylation of gem-Difluorocyclopropanes:
Switching Regioselectivity via Simple
Hydrazones
A highly effective Pd-catalyzed defluor-
inative alkylation of gem-difluoro-
cyclopropane with branched selectivity
was achieved by using a cooperative
strategy that integrated the unique tri-
functional character of hydrazones with
Pd/NHC catalysis.
Angew. Chem. Int. Ed. 2021, 60, 2 – 9
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org
&&&&
These are not the final page numbers!