Rhodium Catalyzed Regioselective C?H Allylation of Simple Arenes via C?C Bond Activation of Gem-difluorinated Cyclopropanes

Article abstract of DOI:10.1002/anie.202016258

Herein, we report a rhodium catalyzed directing-group free regioselective C?H allylation of simple arenes. Readily available gem-difluorinated cyclopropanes can be employed as highly reactive allyl surrogates via a sequence of C?C and C?F bond activation, providing allyl arene derivatives in good yields with high regioselectivity under mild conditions. The robust methodology enables facile late-stage functionalization of complex bioactive molecules. The high efficiency of this reaction is also demonstrated by the high turnover number (TON, up to 1700) of the rhodium catalyst on gram-scale experiments. Preliminary success on kinetic resolution of this transformation is achieved, providing a promising access to enantio-enriched gem-difluorinated cyclopropanes.

Full text of DOI:10.1002/anie.202016258

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 10626–10631
International Edition:
German Edition:
doi.org/10.1002/anie.202016258
doi.org/10.1002/ange.202016258
À
C C Bond Activation
À
Rhodium Catalyzed Regioselective C H Allylation of Simple Arenes
via C C Bond Activation of Gem-difluorinated Cyclopropanes
À
Zhong-Tao Jiang, Jiangkun Huang, Yaxin Zeng, Fangdong Hu, and Ying Xia*
Abstract: Herein, we report a rhodium catalyzed directing-
À
group free regioselective C H allylation of simple arenes.
Readily available gem-difluorinated cyclopropanes can be
employed as highly reactive allyl surrogates via a sequence of
À
À
C C and C F bond activation, providing allyl arene deriva-
tives in good yields with high regioselectivity under mild
conditions. The robust methodology enables facile late-stage
functionalization of complex bioactive molecules. The high
efficiency of this reaction is also demonstrated by the high
turnover number (TON, up to 1700) of the rhodium catalyst on
gram-scale experiments. Preliminary success on kinetic reso-
lution of this transformation is achieved, providing a promising
access to enantio-enriched gem-difluorinated cyclopropanes.
A
llylarene moieties widely exist in a wide range of natural
products and medicinally relevant compounds, and they can
also serve as useful handles to access diversified functional
groups due to the versatile reactivity of the allyl function-
ality.[1,2] Therefore, the development of straightforward and
efficient method for the synthesis of allylarenes has contin-
uously caught the attention of synthetic chemists.[3–9] Tradi-
tional methods including Friedel–Crafts-type allylations
(Scheme 1a) and cross-coupling reactions between aryl and
allyl fragments provide reliable tools for the synthesis of
allylarenes; however, they either suffer from unsatisfied
regioselectivity and bias for electron-rich substrates, or
require the use of pre-functionalized coupling partners,
respectively.[3,4]
À
Scheme 1. Transition-metal catalyzed C H Allylation of Arenes and
Related Reactions. TM, transition metal; EDG, electron-donating
group; DG, directing group; Nu, nucleophiles, including amines,
phenols, alcohols, terminal alkynes and some activated carbon nucle-
ophiles.
One tactic to overcome such limitations is the use of
À
chelation-assisted C H activation protocol, which has
À
emerged as a powerful and efficient alternative in the
of allylarenes is DG-free C H allylation of simple arenes,
[10]
À
formation of C C bonds in modern organic synthesis.
Enabled by a suitable DG (directing group), numerous
catalytic reactions have recently been developed to achieve
which can avoid the laborious installation and removal of
DGs.[8,9] While attractive and promising, the DG-free proto-
col is majorly restricted in a bunch of polyfluoroarenes, in
À
À
ortho-allylation of arenes through site selective C H bond
which the increased acidity of C H bonds in electron-
activation (Scheme 1b).[5,6] Of note that the meta-allylation of
arenes have also been realized through elaborate design of
the DGs.[7] Another strategy for the straightforward synthesis
deficient arenes is the key for such transformations (Sche-
me 1c).[8] While significant extension of this strategy to non-
polyfluoroarenes have been explored, it suffered from harsh
conditions and unsatisfied catalytic efficiency.[9] Thus, the
development of general and efficient method on selective
allylation of simple arenes is still challenging.
[*] Z.-T. Jiang, J. Huang, Y. Zeng, Prof. Dr. Y. Xia
West China School of Public Health and West China Fourth Hospital,
and State Key Laboratory of Biotherapy, Sichuan University
Chengdu 610041 (China)
À
On the other hand, transition metal catalyzed C C bond
activation have persistently drawn attention owing to the
conversion of C C bond into highly active C-M (M = metal)
À
E-mail: xiayingscu@scu.edu.cn
bond which can be easily transformed to manifold function-
Prof. Dr. F. Hu
alities.[11] Cyclopropane derivatives are privileged substrates
School of Chemistry and Chemical Engineering, Linyi University
Linyi 276005 (China)
À
for C C activation taking advantage of their high ring-strain
property.[12,13] Specifically, Fu and co-workers pioneered the
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.202016258.
use of gem-difluorinated cyclopropanes[14] as allyl surrogates
À
À
in cross-coupling reactions via a sequence of C C and C F
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bond activation under palladium catalysis (Scheme 1d),[15]
allylation reaction didnꢀt happen without the involvement of
and the nucleophiles that can be coupled were subsequently
expanded by Fu and other research groups.[16,17] We conceived
that such fluorinated allyl metal species would be highly
electrophilic due to the biggest electronegativity of the
[Rh(CO)2Cl]2, rac-BINAP or AgBF4 (entry 2). Only trace
amount or even no products could be generated when the
solvent was replaced with 1,2-dichloroethane, 1,4-dioxane or
toluene (entries 3–5). Other rhodium pre-catalysts, such as
[Rh(C2H4)2Cl]2, [Rh(cod)Cl]2 or [Rh(PPh3)3Cl], proved to be
much less effective than [Rh(CO)2Cl]2 (entries 6–8). It was
revealed that rac-BINAP was the most suitable ligand in this
transformation at current stage, while other ligands including
PPh3, dppf and IMes gave no or low yield of the product
(entries 9–11). To gain more insights on the role of the silver
salt in this transformation, the effect of some typical silver
additives was then explored (entries 12–14). No product was
detected by using Ag2O as the additive (entry 12). As
expected, AgOTf or AgNTf2 showed considerable reactivity
for the transformation, providing the allylation product in
respectively 32% and 53% yield with the same regioselec-
tivity (entries 13 and 14). Finally, under silver-free conditions
using NaB(3,5-di-CF3C6H3)4 as the additive, conversion to the
product was observed albeit in very low yield; note that the
yield can be improved to 61% under an elevating reaction
temperature, which indicated that the silver salt only served as
halide scavenger and was not involved in the catalytic cycle of
the allylation transformation (entry 15).
À
fluorine substituent, which was expected to enable C H
allylation of simple arenes in high efficiency under mild
conditions. Herein, we discovered that rhodium was a capable
catalyst for our hypothesis, and a wide range of simple arenes,
including electron-rich and -deficient ones, can undergo
À
aromatic C H allylation with gem-difluorinated cyclopro-
panes (Scheme 1e).
To initiate the proposed allylation reaction, (2,2-difluor-
ocyclopropyl)benzene 1a and anisole 2a were selected as the
model substrates for condition optimizations. In the presence
of 1 mol% of [Rh(CO)2Cl]2, 2 mol% of rac-BINAP (racemic-
1,1’-binaphthyl-2,2’-diphenyl phosphine), 10 mol% of AgBF4
and chlorobenzene as the solvent under room temperature
(22 to 328C), the allylation process occurred smoothly in
excellent yield with good regioselectivity. The major product
À
3a comes from the para-C H allylation process, which was
isolated in 86% yield; and the ortho-allylated product 3a’ was
only observed in about 5% yield (entry 1, Table 1). The
Having established the optimized reaction conditions, we
then explored the substrate scope (Scheme 2). First, the scope
of the gem-difluorinated cyclopropane was tested with anisole
2a as the arene partner (Scheme 2a). The aryl of the gem-
difluorinated cyclopropanes bearing electron-donating
groups afforded the desired products in moderate to excellent
yields with good regioselectivity under the optimized con-
ditions (3a–3 f). Among them, meta- (3e) and sterically
hindered ortho-substituted (3 f) substrates afforded compa-
rable results. The substrate containing a strong electron-
donating group gave the corresponding product in decreased
yield, presumably due to the competition between the two
methoxyl-containing arenes (3d). When an electron-with-
drawing group was substituted on the aryl of the gem-
difluorinated cyclopropanes, elevating the reaction temper-
ature was adopted to obtain a good yield of the corresponding
Table 1: Optimization Studies.[a]
Entry
Variations
r.r.
Yield[c]
(3a:3a’)[b]
1
standard conditions
19/1
94%
(86%)[d]
0%
2
w/o [Rh(CO)2Cl]2 or rac-BINAP or
AgBF4
–
3
4
5
6
1,2-dichloroethane instead of PhCl
1,4-dioxane instead of PhCl
PhMe instead of PhCl
–
–
–
–
trace
0%
trace
trace
À
C H allylation products; as expected, the regioselective ratio
[Rh(C2H4)2Cl]2 instead of
[Rh(CO)2Cl]2
of these reactions decreased to some extent (3g–3l). Naph-
thyl cyclopropanes were well tolerated, in which the reaction
of 1-naphthyl one required a higher temperature, presumably
due to the sterical hindrance (3m, 3n). Besides aryl sub-
stituted gem-difluorinated cyclopropanes, alkyl substituted
ones were competent substrates for this transformation,
providing dialkyl substituted fluorinated alkenes in moderate
yields under an elevated reaction temperature (3o, 3p). Of
note that vinyl substituted cyclopropane exhibited similar
reactivity to deliver fluorinated diene as the product in 70%
yield with excellent regioselectivity (3q).
7
8
9
10
11
12
13
14
15[e]
[Rh(cod)Cl]2 instead of [Rh(CO)2Cl]2
[Rh(PPh3)3Cl] instead of [Rh(CO)2Cl]2
PPh3 instead of rac-BINAP
dppf instead of rac-BINAP
IMes instead of rac-BINAP
Ag2O instead of AgBF4
AgOTf instead of AgBF4
AgNTf2 instead of AgBF4
NaB(3,5-di-CF3C6H3)4 instead of
AgBF4
–
–
–
–
19/1
–
0%
12%
0%
trace
9%
0%
32%
53%
18/1
19/1
19/1 (8/1) 5% (61%)
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), [Rh] (2 mol%),
ligand (4 mol%) and additive (10 mol%) in solvent (0.2 mL) under N2
atmosphere at rt (22–328C) for 12 h. [b] The ratio was measured by GC-
MS. [c] Combined yield of 3a and 3a’ determined by 1H NMR using
1,1,2,2-tetrachloroethane as internal standard. [d] The number in
parenthesis was the isolated yield of the major product 3a. [e] The
number in parenthesis was the result of the reaction run at 608C. dppf,
1,1’-bis(diphenyphosphino)ferrocene; IMes, 1,3-bis(2,4,6-trimethylphe-
nyl)imidazol-2-ylidene.
After investigating the scope of the gem-difluorinated
cyclopropanes, the reactivity of the arenes was then fully
evaluated (Scheme 2b). The simplest arene, benzene, can
À
undergo aromatic C H allylation giving product 4a in 87%
yield under modified conditions. Chemical feed-stock arenes
such as toluene, xylenes, mesitylene and naphthalene were
well tolerated to afford the corresponding products 4b–4h in
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À
Scheme 2. Substrate Scope of the Aromatic C H Allylation Reactions. Unless otherwise noted, reactions were run on 0.2 mmol scale under the
standard conditions depicted in entry 1, Table 1. The regioselectivity was over 20>1 if not noted. [a] Combined yields of two isomers are given.
[b] Arene (1.0 mmol) was used. [c] Arene (2.0 mL) instead PhCl as solvent, [Rh(CO)2Cl]2 (2.5 mol%) and rac-BINAP (5 mol%) were used. [d] Arene
(0.2 mL) was used as solvent. [e] Arene (0.4 mL) was used as solvent. [f] Arene (0.6 mmol) was used. [g] Gem-difluorinated cyclopropane
(0.22 mmol) and arene (0.2 mmol) were used. [h] Gem-difluorinated cyclopropane (0.3 mmol) and arene (0.2 mmol) were used. [i] PhCl (0.8 mL)
was used. [j] Arene (2.0 mL) instead PhCl as solvent, [Rh(CO)2Cl]2 (5 mol%), rac-BINAP (10 mol%) and AgBF4 (20 mol%) were used. [k] Gem-
difluorinated cyclopropane (0.1 mmol), [Rh(CO)2Cl]2 (5 mol%), rac-BINAP (10 mol%), AgBF4 (20 mol%), arene (1.0 mL) as solvent were used.
70–93% yields with moderate to good regioselectivity. As
of anisole (4i and 4j). Di-substituted arenes were suitable
À
expected, other alkyl phenyl ethers can undergo C H
allylation with similar efficiency compared with the reaction
substrates to provide the corresponding tri-substituted arenes
À
in moderate to good yields (4k–4p), in which the C H
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allylation occurred at the ortho-position when the para-
À
position was blocked (4p). Meanwhile, the C H allylation
reaction can also be expanded to free phenols, providing the
corresponding products 4q–4v in 60–90% yields; as a sharp
comparison, the free phenol would undergo O-allylation
under palladium catalysis that is described in Scheme 1d.[15a]
Aniline derivatives were proved to be competent substrates
to afford the desired product in excellent yield with moderate
À
to good regioselectivity, in which the para-C H allylation was
still the major reaction pathway even though a chelating
group is contained in the arene (4w–4y). Finally, it was found
À
that a bunch of electron-deficient arenes can also undergo C
H allylation under an elevated reaction temperature to give
the corresponding products in up to 97% yield (4aa–4ad).
Note that high para-selectivity of fluorobenzene was observed
in this rhodium catalysis (4aa and 4ab), while palladium-
catalyzed allylation of fluorobenzene gave excellent ortho-
selectivity in Hartwigꢀs work.[9b]
The practicability of our method was further demon-
strated by the late-stage functionalization of some biological-
ly active compounds (Scheme 3a). Estrone (5a), protected
tyrosine (5b) and D-d-tocophenol (5c) reacted smoothly with
slightly excess of gem-difluorinated cyclopropane 1a to give
the corresponding products in 40–50% yields, in which the
regioselectivity of the reaction of 5c was confirmed through
NOE experiment of the corresponding product.[18] Consider-
ing the high efficiency of this reaction, the test of the TON of
the rhodium catalyst was explored carefully.[18] It was found
that the reaction still worked smoothly on gram-scale when
the loading of the rhodium pre-catalyst was minimized to
0.025 mol%, affording the products in 85% isolated yield
with 1700 TON of the rhodium (Scheme 3b). Moreover, post-
functionalization of 3n was also examined using the allyl
moiety as a versatile handle (Scheme 3c). Hydrogenation of
3n in the presence of Pd/C under a hydrogen atmosphere was
conducted to provide 7a and 7b in 49% and 29% yields,
respectively. Oxidative cross-coupling between 3n and pyra-
zole gave the product 8 in 82% yield.[19] An iron catalyzed C
À
À
H and C C bond cleavage of allylarene was performed with
3n to give fluorinated a,b-unsaturated amide 9 in 63% yield,
in which the product was unambiguously confirmed by X-ray
crystallography.[2a,20] Of note that the regioselectivity of the
latter two transformations was opposite, which might be
explained by the different mechanisms.[2a,19] Finally, we were
delighted to find that this protocal can be expanded to
synthesize chiral gem-difluorinated cyclopropanes with a ee
(enantiomeric excess) value of 78% when using (R)-BINAP
as the ligand by kinetic resolution process, providing a prom-
ising access to enantio-enriched gem-difluorinated cyclopro-
panes (Scheme 3d).
Scheme 3. Synthetic Applications.
Based on our experiments and the previous reports,[15,16]
rhodium species C would be highly electrophilic, which can
À
a
plausible mechanism was proposed as described in
then trigger a C H bond activation of the arene through
Scheme 4. Initially, the pre-catalyst [Rh(CO)2Cl]2 de-dimer-
electrophilic metallation pathway to give complex D. Finally,
a reductive elimination process occurs to afford the desired
allylation product, which regenerates the active catalyst A to
finish the catalytic cycle (An alternative reaction pathway via
Friedel–Crafts-type allylation is less possible, see supporting
information for more detailed discussions).
izes to form a highly active cationic rhodium(I) species A in
the presence of rac-BINAP and AgBF4.[21] A C C bond
À
oxidative addition of the gem-difluorinated cyclopropane
would occur to form rhodium complex B,[12] which then
undergoes a b-fluoride elimination to generate the key
intermediate C. As we have proposed, the fluorinated allyl
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Scheme 4. Plausible Mechanism.
In summary, we have successfully developed a rhodium
catalyzed DG-free allylation of C H bond in simple arenes.
The transformation features the use of gem-difluorinated
cyclopropanes as allyl surrogates via C C bond activation
À
À
process. Fluorinated allyl rhodium species was proposed as
the key intermediate, in which its highly electrophilic nature
enables the high efficiency and good functional group
tolerance of the transformation. This protocol provides
a useful and facile route to access fluorinated allylarenes
from readily available starting materials. The successful late-
stage functionalization of biologically active molecules, the
gram-scale experiment with high TON of the catalyst (up to
1700) and the preliminary success on kinetic resolution
highlight the potential of the methodology in medicinal
chemistry and organic synthesis.
Acknowledgements
This work is supported by “Thousand Youth Talents Plan”
and the start-up funding from Sichuan University. Public
Health and Preventive Medicine Provincial Experiment
Teaching Center at Sichuan University and Food Safety
Monitoring and Risk Assessment Key Laboratory of Sichuan
Province are acknowledged for the support. F.H. acknowl-
edges the National Natural Science Foundation (Grant
21801109), the Natural Science Foundation of Shandong
Province (Grant ZR2018BB019) and the Higher Educational
Science and Technology Program of Shandong Province
(Grant J17KA099) for their financial support.
À
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Conflict of interest
The authors declare no conflict of interest.
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À
À
Keywords: C C bond activation · C H allylation ·
directing-group-free · gem-difluorinated cyclopropane ·
rhodium catalysis
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Manuscript received: December 7, 2020
Revised manuscript received: February 5, 2021
Accepted manuscript online: February 17, 2021
Version of record online: March 30, 2021
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