Palladium-Initiated Radical Cascade Stereoselective Iodofluoroalkylation/Cycloisomerization of Ene-vinylidenecyclopropanes

Article abstract of DOI:10.1002/chem.201601625

A novel and convenient palladium-initiated radical cascade stereoselective iodofluoroalkylation/cycloisomerization of ene-vinylidenecyclopropanes with fluoroalkyl iodides has been developed. The reaction proceeds under mild reaction conditions with high atom economy and stereoselectivity, thereby allowing an efficient access to a variety of difluoromethylated or perfluoroalkylated pyrrolidines tethered with an alkyl iodide. Two plausible radical pathways for the transformation have been proposed on the basis of the results of control experiments and previous reports, which in one case it was thought that palladium(0) was an initiator rather than a catalyst.

Full text of DOI:10.1002/chem.201601625

DOI: 10.1002/chem.201601625
Communication
&
Fluoroalkylation
Palladium-Initiated Radical Cascade Stereoselective
Iodofluoroalkylation/Cycloisomerization of Ene-
vinylidenecyclopropanes
Song Yang,[a] Qin Xu,[a] and Min Shi*[a, b]
Abstract: A novel and convenient palladium-initiated radi-
cal cascade stereoselective iodofluoroalkylation/cycloiso-
merization of ene-vinylidenecyclopropanes with fluoroalk-
yl iodides has been developed. The reaction proceeds
under mild reaction conditions with high atom economy
and stereoselectivity, thereby allowing an efficient access
to a variety of difluoromethylated or perfluoroalkylated
pyrrolidines tethered with an alkyl iodide. Two plausible
radical pathways for the transformation have been pro-
posed on the basis of the results of control experiments
and previous reports, which in one case it was thought
that palladium(0) was an initiator rather than a catalyst.
Figure 1. Representative fluorine containing drugs and bioactive molecules.
Organofluorine compounds are widely used in medicine, agri-
culture, and also in life and material sciences because of their
unique metabolic stability, lipophilicity, and biological proper-
ties (Figure 1).[1] Therefore, the development of new synthetic
methods for the incorporation of fluorine or fluorinated moiet-
ies into organic molecules is of significant importance. Numer-
ous methods for the incorporation of fluoroalkyl motifs have
been extensively investigated in the past decades.[2]
During our ongoing investigation on the chemistry of vinyli-
denecyclopropanes (VDCPs),[9] we have developed the FeIII-cat-
alyzed intramolecular cycloisomerization of acetal-VDCPs to
construct a series of halogenated 1,2-disubstituted cyclobu-
tenes tethered with a tetrahydropyrrole (Scheme 1A).[9b] Com-
bined with our previous work on metal-mediated transforma-
tions of VDCPs, we envisaged that ene-VDCPs could be excel-
lent candidates for the exploration of new reaction method in
fluoroalkylation because of their multiple reaction sites. Herein,
we wish to report an intriguing new palladium-initiated radical
cascade iodofluoroalkylation/cycloisomerization of ene-VDCPs
with fluoroalkyl iodide, which affords an easy and efficient
As ubiquitous feedstock materials and good radical recep-
tors, reacting enynes with fluoroalkyl halides (Br or I) has been
achieved before using a radical initiator, such as AIBN,[3] Et3B,[4]
Na2S2O4,[5] or light.[6] At the same time, transition-metal-mediat-
ed or catalyzed fluoroalkylation has emerged as a highly effi-
cient alternative pathway to fluorination for the introduction
of fluorine-containing structural motifs into organic molecules
in recent years.[7] Despite significant advances in this area,[8]
more concise, mild, and atom-economical fluoroalkylation
methods for synthesizing complex organic compounds remain
highly desired.
[a] S. Yang, Dr. Q. Xu, Prof. Dr. M. Shi
Key Laboratory for Advanced Materials and Institute of Fine Chemicals
East China University of Science and Technology
Meilong Road No. 130, Shanghai, 200237 (P. R. China)
[b] Prof. Dr. M. Shi
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
354 Fenglin Road, Shanghai 200032 (P. R. China)
E-mail: mshi@mail.sioc.ac.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201601625.
Scheme 1. A) FeIII-catalyzed cycloisomerization of acetal-vinylidencyclopro-
panes and B) the current work.
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access to iodine/fluoroalkylation pyrrolidines tethered with an
alkyl iodide and other five- or six-membered-ring heterocyclic
derivatives (Scheme 1B).
an improvement was achieved by decreasing the concentra-
tion of 1a to 0.05 mol/L, giving 2a in 78% yield (Table 1,
entry 17). However, further decrease of the concentration did
not raise the yield of product 2a. Additionally, no product was
formed without palladium catalyst or ligand (Table 1, entry 20).
Interestingly, the yields of 2a decreased distinctly if the reac-
tion was conducted without Cs2CO3 or phosphine ligands
(Table 1, entries 21 and 22). It has been reported that Cs2CO3
alone is sufficient to activate fluoroalkyl iodides at 608C, lead-
ing to the formation of fluoroalkyl radicals.[7g] Thus, we thought
that Cs2CO3 alone could activate fluoroalkyl iodides in this re-
action to give the desired product. Finally, the use of 1a
(1.0 equiv), PdCl2(PPh3)2 (10 mol%), Xantphos (20 mol%), and
Cs2CO3 (2.0 equiv) with ethyl difluoroiodoacetate (2.0 equiv) in
the presence of dioxane (2.0 mL) under an argon atmosphere
at 508C for 12 h was considered as the optimal reaction condi-
tions.
Our initial studies focused on the palladium-initiated reac-
tion of readily available ethyl difluoroiodoacetate with ene-
VDCP 1a. The use of ethyl difluoroiodoacetate is of interest be-
cause of its applications arising in various areas, including me-
dicinal chemistry. For instance, the difluoromethylene moiety
(CF2R, CF2H) has been recognized as a potential bioisostere of
hydroxy[10] or thiol[11] groups, and acts as a lipophilic hydrogen-
bond donor.[12] To our delight, an expected product 2a was
isolated in 58% yield as a single stereoisomer after 12 h, in the
presence of PdCl2(PPh3)2 (10 mol%), DPEPhos (20 mol%), and
Cs2CO3 (2.0 equiv) in 1,4-dioxane (1.0 mL) at 508C under an
argon atmosphere (Table 1, entry 1). The structure of 2a was
unambiguously assigned by X-ray diffraction.[13,14] Inspired by
this result, different palladium catalysts were evaluated for this
transformation. In contrast to PdCl2(PPh3)2, other catalysts
failed to show higher catalytic ability (Table 1, entries 2–4).
Among the ligands surveyed, we found that Xantphos was the
most efficient one, promoting an increasing yield to 69%
(Table 1, entries 5–8). A subsequent survey on several represen-
tative bases and solvents indicated that Cs2CO3 and 1,4-diox-
ane were still the best choice (Table 1, entries 9–16). Pleasingly,
To demonstrate the substrate scope of this method, a variety
of ene-VDCPs were examined and the results are shown in
Scheme 2. With ene-VDCPs 1b–i as the substrates (R=primary
or secondary alkyl groups; X=TsN or BsN anchor), the desired
products 2b–i were obtained in good yields ranging from
73% to 81% with good stereoselectivity. When ene-VDCP 1j,
with O as an anchor, was used as substrate, the yield of de-
sired product 2j slightly decreased to 58%. Extending the
carbon chain to alkene moiety as a (CH2)2 tether, the desired
product 2k could be given in 50% with 20% byproduct 2k’.
Notably, 2k’ may be the precursor of 2k. However, when ene-
VDCP 1l, bearing a (CH2)3 carbon chain to the alkene moiety,
was employed, no reaction occurred under the standard condi-
tions. The inferior results for 1k and 1l are presumably due to
the fact that forming six or seven-membered rings is difficult
Table 1. Screening conditions for iododifluoromethylation/cycloisomeriza-
tion of ene-VDCP 1a.
Entry[a]
Initiator
Ligand
Base
Solvent
Yield[%][b]/2a
1
2
3
4
5
6
7
8
PdCl2(PPh3)2
Pd(OAc)2
PdCl2
DPEPhos
DPEPhos
DPEPhos
DPEPhos
JohnPhos
Xantphos
DPPF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
58
42
47
53
27
69
60
33
trace
30
complex
complex
40
trace
35
52
Pd(PPh3)4
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
(Æ)-BINAP Cs2CO3
9
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
K2CO3
Na2CO3 dioxane
10
11
12
13
14
15
16
17
18[d]
19[c,e]
20
21
22
23[f]
NaOAc
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
–
dioxane
DMF
MeCN
Toluene
DCE
DCM
dioxane 78
PdCl2(PPh3)2 Xantphos
PdCl2(PPh3)2
PdCl2(PPh3)2
–
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
Xantphos
Xantphos
–
Xantphos
–
–
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
72
52
trace
51
31
Cs2CO3
Cs2CO3
64
[a] Reaction conditions: 1a (0.1 mmol), ethyl difluoroiodoacetate (2.0 equiv),
catalyst (10 mol%), ligand (20 mol%), base (2.0 equiv) and solvent (1.0 mL)
were used. [b] Yield of isolated product. [c] 2.0 mL dioxane was employed.
[d] 3 mL dioxane was employed. [e] ICF2CO2Et (4 equiv) was employed.
[f] 1.0 equiv PdCl2(PPh3)2 was employed.
Scheme 2. Substrate scope of the iododifluoromethylation/cycloisomeriza-
tion of ene-VDCPs. Reaction conditions: 1 (0.2 mmol), ethyl difluoroiodoace-
tate (2 equiv), PdCl2(PPh3)2 (10 mol%), Xantphos (20 mol%), Cs2CO3 in diox-
ane (4.0 mL) at 508C for 10–20 h, yield of isolated product.
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and needs higher energy than that of five-membered ring. In
all these cases, the desired products were isolated as a single
stereoisomer. Interestingly, when ene-VDCP 2m (R1 =Me) was
applied under the standard conditions, the corresponding
product 2m could be obtained in 70% yield. It was notable
that the product 2m contains a pair of diastereoisomers with
a 2:1 ratio and the relative configuration of syn-2m was deter-
mined by nuclear Overhauser effect spectroscopy (see the Sup-
porting Information).
(Table 2, entry 8). Moreover, the yield of 3a decreased in the
absence of ligand (Table 2, entry 10).
With the optimized reaction conditions in hand, the reac-
tions of fluoroalkyl iodides with other ene-VDCPs 1 were then
carried out to define the generality of this procedure, and the
results are shown in Scheme 3. Similarly, using ene-VDCPs 1b–
1j as the substrates, the desired perfluoroalkylated products
To further investigate the practicability of this reaction, other
fluoroalkyl iodides were surveyed as well. Gratifyingly, we
found that when perfluorobutyl iodide was used, the corre-
sponding perfluoroalkylated product 3a was successfully ob-
tained in 37% yield along with 17% of byproduct 4a (Table 2,
Table 2. Screening conditions for iodoperfluoroalkylation/cycloisomeriza-
tion of ene-VDCP 1a.
Entry[a] Initiator
Ligand
Additive (equiv) Yield[%][b]/3a:4a[c]
1
2
3
4
5
6
7
8
PdCl2(PPh3)2 Xantphos
–
–
–
–
–
54 (2.1:1)
67 (3.5:1)
73 (3.3:1)
62 (3.7:1)
79 (4.2:1)
85 (>20:1)
81 (>20:1)
trace
Pd(PPh3)4
PdCl2
Xantphos
DPEPhos
dppf
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
(Æ)-BINAP
Scheme 3. Substrate scope of the iodoperfluoroalkylation/cycloisomeriza-
tions of ene-VDCPs. Reaction conditions: 1 (0.2 mmol), I(CF2)3CF3 (2 equiv),
Pd(PPh3)4 (10 mol%), (Æ)-BINAP (20 mol%), Cs2CO3 and H2O (10 equiv), in Di-
oxane (2.0 mL) at 508C for 10–20 h, yield of isolated product.
[a] Pd(MeCN)2Cl2 (10 mol%) was employed.
(Æ)-BINAP H2O (10)
(Æ)-BINAP H2O (100)
(Æ)-BINAP LiCl (5)
(Æ)-BINAP 4 ꢁ
9[d]
10
69 (1.2:1)
60 (>20:1)
-
H2O (10)
[a] Reaction conditions: 1a (0.02 mmol), I(CF2)3CF3 (2 equiv), catalyst
(10 mol%), ligand (20 mol%), Cs2CO3 (2.0 equiv) and dioxane (2.0 mL) were
used. [b] Yield of isolated 3a and 4a. [c] Determined by 19F NMR spectros-
copy. [d] 4 ꢁ molecular sieve (50 mg) was added.
3b–3g were obtained in good to excellent yields, ranging
from 72% to 90%. When R2 was bulky cyclohexyl,
PdCl2(MeCN)2 was employed as the initiator and the corre-
sponding products 2h and 2i could also be afforded in 68%
and 66% yields, respectively. A moderate yield was obtained
when ene-VDCP 1j was used as substrate. Satisfactorily, 3k
and 3m could be smoothly afforded as single diastereoisomers
in 55% and 67% yields under the standard conditions, respec-
tively. However, none of the desired seven-membered-ring
product was formed when 1l was employed as substrate. A
different perfluoroalkyl iodide was also investigated. When per-
fluoro-1-iodohexane was utilized in this reaction, the desired
product 3n was produced in 74% yield. In all these cases, the
desired products were isolated as a single stereoisomer.
entry 1). The structure of 4n (Rf =C6F13) was unambiguously as-
signed by X-ray diffraction.[13,14] To improve the reaction selec-
tivity and yield of 3a, different palladium catalysts, bases, sol-
vents, and additives were surveyed. Detailed results are briefly
summarized in Table 2 (for more details, see the Supporting In-
formation, Table S1). We found that Pd(PPh3)4 and (Æ)-BINAP
were superior to other palladium catalysts and ligands (Table 2,
entries 1–5). Interestingly, the addition of 10.0 equiv of deion-
ized water to the reaction mixture leads to selective formation
of 3a in 85% yield (Table 2, entry 6). However, increasing the
employed amount of water further did not give a better result
(Table 2, entry 7). Besides, the addition of 4 ꢁ molecular sieves
did not improve the yield of 4a. The role of water cannot be
clearly explained at the present stage, but it seems that the
dehydroiodination process was inhibited. It has been reported
that bulky ligands and other additives could suppress b-hy-
dride elimination from alkylpalladium halides.[15] When
10 equiv of LiCl was added, only trace of 3a could be detected
on the basis of monitoring with thin-layer chromatography
In the previous reports with regard to the Pd-catalyzed simi-
lar fluoroalkylation/cycloisomerization, iodofluoroalkyl alkene
intermediates were involved in the related transformation.[7b–d]
Thus, it is worth considering that the exist of (alkyl)PdI inter-
mediates may produce the target products via reductive elimi-
nations. Although iodinated alkylpalladium(II) complexes have
recently become synthetically useful for constructing carbon–
carbon bonds and carbon-heteroatom bonds through transi-
tion-metal-catalyzed cross-coupling reactions.[16] However, the
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iodinated alkylpalladium complex is believed to be highly reac-
tive owing to the absence of stabilizing electronic interaction
with metal d-orbitals.[17] The fast and thermodynamically fa-
vored b-hydride elimination is the predominant process for the
(alkyl)PdI species. Only a few examples of reductive elimination
of iodinated alkylpalladium-containing syn-b-hydrogen atoms
have been reported.[16a,18] In general, the formation of (alkyl)PdI
intermediates not seems to be possible in this case.
To gain more mechanistic insight into the present reaction,
several control experiments were performed (Scheme 4).
Scheme 5. An outline of two plausible mechanisms for the formation of 2 or
3.
ed radical cascade iodofluoroalkylation/cycloisomerization of
ene-VDCPs with fluoroalkyl iodides are presented in Scheme 5.
In one mechanism (path I), a fluoroalkyl radical Rf. and a PdI
specie are generated through a single electron transfer (SET)
between Rf-I and Pd0. Then, the addition of the Rf. radical to
the double bond of ene-VDCP generates the radical intermedi-
ate A. Subsequently, a 5-exo-trig cyclization occurs to afford
methylenecyclopropane (MCP) radical intermediate B, which
undergoes an intramolecular radical rearrangement with the
ring-opening of cyclopropane to give the corresponding radi-
cal intermediate C. Finally, the intermediate C is able to ab-
stract the iodide from LnPdII, thus leading to the formation of
product and regeneration of Pd0.[19] Besides, another plausible
mechanism has been also proposed (path II). The same inter-
mediate C is produced after an intramolecular radical rear-
rangement. However, this intermediate C reacts with Rf-I to
Scheme 4. Control experiments for mechanistic studies.
When a reaction mixture of 1a and perfluorobutyl iodide was
treated under the standard conditions in the presence of the
radical scavenger TEMPO (2,2,6,6-tetramethylpiperidinyloxy)
(2.0 equiv), no product was detected, implying that a SET pro-
cess is involved in the catalytic cycle. When Pd(PPh3)4 was re-
placed by AIBN or FeCl2,[7f] the reaction also proceeded very
well and afforded 3a in 46% and 55% yields, respectively, ren-
dering the involvement of a radical process. However, only
FeCl2 (20 mol%) could not initiate this reaction if without the
use of Cs2CO3 (Supporting Information, Table S2). Furthermore,
when 3a (0.1 mmol) was used as substrate directly in the pres-
ence of Pd(PPh3)4 (10 mol%), (Æ)-BINAP (20 mol%), and Cs2CO3
(2.0 equiv) in 1,4-dioxane (1.0 mL) at 508C or 808C, 4a could
be obtained in 45% or 65% yields respectively. In the absence
of Pd(PPh3)4 and (Æ)-BINAP however, the transformation of 3a
proceeded smoothly to afford 4a in a similar yield. Thus, 4a
was believed to be formed by a base-assisted dehydroiodina-
tion instead of the b-H elimination of alkylpalladium iodide in-
termediate. These results shed some lights on the insight into
the mechanism of this Pd initiated reactions.
C
generate the Rf radical again and produce the corresponding
iodofluoroalkylation product 2 or 3. In this radical process, Pd0
acts as an initiator rather than a catalyst.
As for the observed high diastereoselectivities, a hypothesis
based on steric hindrance has been proposed in Scheme 6.
Placing the alkyl substituent R2 and Rf away from each other
minimizes steric interactions and provides intermediate B as
syn-configuration. Furthermore, it is also possible that the
LnPdII species or Cs2CO3 may be involved in the 5-exo-trig cyc-
On the basis of the above experiments and the relevant re-
sults reported, two of the plausible pathways for the Pd-initiat-
Scheme 6. Hypothesis for the diastereoselectivity of the cycloisomerization.
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Scheme 7. Further transformation of 3a.
In conclusion, we have developed a palladium-initiated radi-
cal cascade stereoselective iodofluoroalkylation/cycloisomeriza-
tion of ene-vinylidenecyclopropanes with fluoroalkyl iodides,
which can efficiently synthesize a variety of useful iododifluor-
omethylated or iodoperfluoromethylated pyrrolidines tethered
with an alkyl iodide and other five or six-membered heterocy-
clic derivatives. These five or six-membered fluorine-containing
heterocyclic compounds may be used as potential intermedi-
ates in organic synthesis and medicinal chemistry. Beside, two
plausible mechanisms were proposed based on the results of
control experiments and relevant previous reports. Further
work will be devoted to applying this new method to synthe-
size biologically active products.
Acknowledgements
This work was supported by the Joint NSFC-ISF Research Pro-
gram, jointly funded by the National Natural Science Founda-
tion of China and the Israel Science Foundation. We are also
grateful for the financial support from the National Basic Re-
search Program of China (973)-2015CB856603 and the National
Natural Science Foundation of China for financial support
(20472096, 21372241, 21361140350, 20672127, 21102166,
21121062, 21302203, 20732008 and 21572052).
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Keywords: alkyl iodides · cyclopropane · difluoromethylation ·
ene-vinylidenecyclopropanes · palladium
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Received: April 7, 2016
Revised: May 2, 2016
Published online on && &&, 0000
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ÝÝ These are not the final page numbers!

Communication
COMMUNICATION
A radical cascade stereoselective iodo-
fluoroalkylation/cycloisomerization of
ene-vinylidenecyclopropanes with fluo-
roalkyl iodides and initiated by palladi-
um has been developed. This method
affords a variety of difluoromethylated
or perfluoroalkylated pyrrolidines teth-
ered with an alkyl iodide.
&
Fluoroalkylation
S. Yang, Q. Xu, M. Shi*
&& – &&
Palladium-Initiated Radical Cascade
Stereoselective Iodofluoroalkylation/
Cycloisomerization of Ene-
vinylidenecyclopropanes
Chem. Eur. J. 2016, 22, 1 – 7
www.chemeurj.org
7
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ