Palladium-Catalyzed Fluoroalkylative Cyclization of Olefins

Article abstract of DOI:10.1021/acs.orglett.6b03865

A palladium-catalyzed fluoroalkylative cyclization of olefins with readily available R_f-I reagents to afford the corresponding fluoroalkylated 2,3-dihydrobenzofuran and indolin derivatives with moderate to excellent yields is reported. This novel procedure provides an efficient method for the construction of C_sp³-CF₂ and C-O/N bonds in one step. A wide range of functional groups are tolerated. It is proposed that a radical/SET (single electron transfer) pathway proceeding via the fluoroalkyl radical may be involved in the catalytic cycle.

Full text of DOI:10.1021/acs.orglett.6b03865

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Fluoroalkylative Cyclization of Olefins
Jianhua Liao,†,‡ Lianfeng Fan,† Wei Guo,† Zhenming Zhang,† Jiawei Li,† Chuanle Zhu,† Yanwei Ren,†
Wanqing Wu,*,† and Huanfeng Jiang*,†
†Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering,
South China University of Technology, Guangzhou 510640, P. R. China
‡School of Pharmaceutical Sciences, Gannan Medical University, Ganzhou, Jiangxi 341000, China
S
* Supporting Information
ABSTRACT: A palladium-catalyzed fluoroalkylative cycliza-
tion of olefins with readily available Rf−I reagents to afford the
corresponding fluoroalkylated 2,3-dihydrobenzofuran and
indolin derivatives with moderate to excellent yields is
reported. This novel procedure provides an efficient method
3
for the construction of Csp −CF2 and C−O/N bonds in one
step. A wide range of functional groups are tolerated. It is
proposed that a radical/SET (single electron transfer) pathway proceeding via the fluoroalkyl radical may be involved in the
catalytic cycle.
Scheme 1. Methods for Incorporation of Fluoroalkyl Groups
otivated by diverse applications in agrochemistry,
M
pharmacy, and materials science, substantial efforts have
been dedicated to the development of efficient protocols of
organofluorine compounds.1 Among thecommonly encountered
fluoroalkyl groups, the difluoromethylene (CF2) moiety has been
tremendously investigated in recent years owing to its unique
applications in drug discovery and life science.2,3 For instance, it
canbeservedasapotentialbioisostereofhydroxylorthiolgroups,
as well as a carbonyl group.3 Given the importance of the CF2
functional moiety in synthetic and medicinal chemistry,
significant recent efforts have been reported for the new synthetic
procedures.4 Recently, the transition-metal based protocols have
2
been focused on the exploration of the efficient Csp −CF2 bond
formation via cross-coupling with aryl boronic acid,5 aryl halides,6
heteroaryl C−H bonds,7 styrenes,8 and α,β-unsaturated carbox-
ylicacids (Scheme 1, eqs 1and2).9 Morerecently in2016, elegant
2
works of different transition-metals-induced Csp −H difluorome-
thylation of aldehyde-derived hydrazones to afford the function-
alizeddifluoromethylketonehydrazoneshavebeenreported, with
some evidence for a SET-initiated radical process.10 Compared
catalysis.15 Afterward, an efficient intramolecular amino- and oxy-
difluoromethylation process of unactivated alkenes with
HCF2SO2Cl as the HCF2 radical source by photoredox-catalyzed
was proposed by the Dolbier group.16 Hence, it is highly desirable
to explore a general and practical method for construction of C−
CF2 and C−C/X bonds.
2
with interest in the construction of Csp −CF2 bonds, method
3
development for Csp −CF2 bond generation has received less
attention (Scheme 1, eq 3).11 In 2013, Wolf and co-workers
documented that copper(II)-induced addition of α,α-difluor-
oenolates to aldehydes with high yields and ee values.12 Efficient
Mukaiyama−Michael addition of fluorinated enol silyl ethers to
tetrasubstituted olefins catalyzed by a chiral secondary amine
phosphoramide was proposed by Zhou group in 2015.13
Inspired by these advances and based on our previous work,17
we envisioned thatsince oxidative addition of iododifluoromethyl
reagents to Pd(0) is feasible, then electrophilic palladation of
alkenes with the resulting Pd(II) complex by a subsequent
nucleophile reaction might represent a possible alternative
3
Previously, the silver-mediated Csp −CF2 bond formation
procedure has been investigated by the Hao group.14 However,
3
strategy to realize the construction of Csp −CF2 and C−O/N
despite a variety of significant advances for the construction of
bonds in a one-step manner. Fortunately, a palladium-catalyzed
2
3
Csp −CF2 (or Csp −CF2) bonds, there are fewer protocols for C−
CF2 and C−X (X = heteroatom) bonds in a one-step synthesis. In
2015, the Stephenson group established a new approach for the
halodifluoromethylation of alkenes via visible light photoredox
Received: December 27, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03865
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Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
b
entry
catalyst
Pd2(dba)3
ligand
base
solvent
yield (%)
c
1
Xantphos
Xantphos
Xantphos
Xantphos
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
t-BuOK
Et3N
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
31
48
28
50
55
56
60
65
54
10
65
25
28
78
69
57
trace
2
PdCl2(CH3CN)2
PdCl2(PPh3)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
3
4
d
5
DPEPhos
PPh3
6
e
7
dppe
f
8
dppf
9
dppf
dppf
dppf
dppf
dppf
dppf
dppf
dppf
dppf
10
11
12
13
14
15
16
17
CF3CO2Na
NaOAc
KOAc
K3PO4
CsOAc
LiOAc
a
A mixture of 1aa (0.15 mmol, 1 equiv), 2a (0.3 mmol, 2 equiv), base (0.3 mmol, 2 equiv), catalyst (7.5 mol %), ligand (15 mol %), and solvent (3
b
c
mL) were sealed in a 25 mL Schlenk tube at 80 °C for 20 h under N2. Yields of the isolated product. Xantphos =
d
e
dimethylbisdiphenylphosphinoxanthene. DPEPhos = bis[2-(diphenylphosphino)phenyl] ether. dppe = 1,2-bis(diphenylphosphino) ethane.
f
dppf = 1,1′-bis(diphenylphosphino) ferrocene.
a,b
coupling of alkenes with iodofluoroalkylated reagents which
affords a variety of dihydrobenzofuran and indoline derivatives
has been developed (Scheme 1, eq 4).
Scheme 2. Substrate Scope of 2-Allylphenols
,
We initiated our investigations using 2-allylphenol 1aa with
ethyl iododifluoroacetate 2a as the substrates. The combination
of 1aa, Pd2(dba)3, Xantphos, and K2CO3 in dioxane at 80 °C for
20 h under a nitrogen atmosphere afforded a modest yield (31%)
of the desired product 3aa (Table 1, entry 1). And the major
byproduct of this transformation is unreacted starting material.
To improve the yield of 3aa, various catalysts were screened.
Delightfully, the use of Pd(PPh3)4 was more effective with the
moderate yield of 50% (Table 1, entry 4). Using dppf as a ligand,
the optimal ligand for this transformation still provided the
desired 3aa in moderate yield (Table 1, entry 8). To complete the
difluoroalkylative cyclization synthesis, a base is necessary to
neutralize the acid generated in the reaction system. Thus, a range
ofsaltswerealsoscreened. Significantly, KOAcwasselectedasthe
optimalbase, givingagoodyieldof3aa(78%)(Table1, entry14).
Additionally, the reaction is very sensitive to solvent and dioxane
is much better than other solvents (see Supporting Information).
With the optimal conditions established, the remaining
substrates were screened to probe the generality of the new
protocol. Gratifyingly, a broad substrate scope was compatible
with the method and displayed excellent chemoselectivity
(Scheme 2). Good yields were obtained with para- and ortho-
substituted aryls. Notably, substrates with both electron-with-
drawing and -donating substituents afforded the products 3aa−ai
in good to excellent yields. Versatile functional groups, such as
halogens, acetyl, nitro, formyl, cyano, hydroxyl, and ether were
tolerated, thus offering opportunities for further transformations.
Significantly, product 3ae proved to be crystalline.18 The relative
stereochemistry of these difluoromethylative cyclization 2,3-
dihydrobenzofuran derivatives were determined by means of
crystallographic analysis. Notably, the multisubstituted aryls
a
Reaction conditions: 1aa (0.15 mmol, 1 equiv), 2a (0.3 mmol, 2
equiv), KOAc (0.3 mmol, 2 equiv), Pd(PPh3)4 (7.5 mol %), dppf (15
mol %), and dioxane (3 mL) was sealed in a 25 mL Schlenk tube at 80
b
c
°C for 20 h under N2. Isolated yields based on 1a. ORTEP
representation with 50% probability thermal ellipsoids of a crystal
structure of 3ae. Isolated yields based on 1ah at the 1 mmol scale.
d
proceeded smoothly to give the corresponding products (3aj−
al). Notably, the product of 3ak has an excellent yield of up to
90%. However, the steric effect of the substituent seemed to have
B
DOI: 10.1021/acs.orglett.6b03865
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Organic Letters
Letter
a b
,
some influence on the reaction (3am). Importantly, the hetroaryl
substrate was also compatible with the transformation (3an).
In view of the importance of perfluoroalkyl moieties, the
possible incorporation of such groups into substrates was
screened (Scheme 3). In general, perfluoroalkylated products
Scheme 4. Substrate Scope of 2-Allylanilines
a b
,
Scheme 3. Substrate Scope of Iodoperfluoroacetates
a
Reaction conditions: 1b (0.15 mmol, 1 equiv), 2 (0.3 mmol, 2 equiv),
CsOAc (0.3 mmol, 2 equiv), Pd(PPh3)4 (7.5 mol %), dppf (15 mol
%), and dioxane (3 mL) were sealed in a 25 mL Schlenk tube at 80 °C
b
for 20 h under N2. Isolated yields based on 1b.
Scheme 5. Preliminary Mechanistic Studies
a
Reaction conditions: 1aa (0.15 mmol, 1 equiv), 2b (0.3 mmol, 2
equiv), KOAc (0.3 mmol, 2 equiv), Pd(PPh3)4 (7.5 mol %), dppf (15
mol %), and dioxane (3 mL) were sealed in a 25 mL Schlenk tube at
b
c
80 °C for 20 h under N2. Isolated yields based on 1a. ORTEP
representation with 50% probability thermal ellipsoids of a crystal
structure of 3bc.
Information). Moreover, when 1,1-diphenylethylene (1 equiv)
was used as a radical scavenger in this reaction, the product 3aa
underwent a dramatic drop in yield of 10%, with the formation of
6in51%yield(determinedbyNMRspectroscopy)(Scheme5,eq
2). These preliminary experiments seem to confirm that a free
CF2CO2Et radical is generated under our standard reaction
conditions.
could react efficiently in moderate to good yields (3ba−be)
(structure 3bc was confirmed by X-ray crystallography).19
Interestingly, a multisubstituted aryl was successfully prepared
in 91% yield (3bf). However, there was less tolerance for
condensed ring and condensed heterocyclic substrates (3bh,
3bi).
To further diversify the protocol, the substrate scope was
expanded to different substituted 2-allylanilines (Scheme 4).
Pleasingly, the difluoroalkylative cyclization of 2-allylanline 1ba
could undergo this transformation with a 40% yield under the
optimal conditions. To complete the indolin synthesis, addition
of a range of acetates was screened, which deeply affected the
transformation (see Supporting Information). Ultimately,
CsOAc was selected as the optimal base. With the optimized
reaction conditions in hand, we assayed the reaction against a
number of substituted 2-allylanlines and were pleased to observe
successful fluoroalkylative cyclization products (4a−4f). Surpris-
ingly, steric hindrance in terms of R2-substitution also underwent
the conversion smoothly to afford product 4g.
In light of these experimental results and previous work,6−10
a
plausible radical/SET pathway is outlined in Scheme 6. The
Scheme 6. Possible Mechanism
To gain some insight into the mechanism of our reaction,
several control experiments were performed to investigate the
possibility of a radical/SET pathway. Our standard coupling
reaction of 1aa with 2a (78%) was thus repeated in the well-
known radical scavenger 2,2,6,6-tetramethyl-1-piperidinoxyl
(TEMPO, 1 equiv). Interestingly, formation of product 3aa was
totally inhibited, and the TEMPO−CF2CO2Et adduct 5 was
process would begin with the formation of an electrophilic
fluoroalkyl radical (A) via a radical/SET pathway from a Pd(0)
complex to ICF2CO2Et with concomitant generation of Pd(I)
complex B. Subsequent electrophilic radical addition of A across
the CC bond of the olefins was a key step and led to the
formation of the carbon free radical C. Further oxidation of the
1
formed in 30% yield as estimated by H, 13C, and 19F NMR
spectroscopy (Scheme 5, eq 1). The reaction was also performed
in the presence of butylated hydroxytoluene (BHT, 1 equiv)
which furnished 3aa in a diminished yield of 27% (see Supporting
C
DOI: 10.1021/acs.orglett.6b03865
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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radicalcomplexCwithPd(I)wouldleadtothePd(II)complexD.
Finally, reductive elimination of D from the α-OH group afforded
the coupling product 3 and recycled the active Pd(0) catalytic
species. However, an alternative pathway with Pd(0) as a radical
initiator followed by an intramolecular SN2 substitution was also
possible (see Supporting Information for details). 2-Allylaniline
substrates would undergo a similar mechanism.
In summary, we have presented a practical Pd(0)-catalyzed
fluoroalkylative cyclization reaction of unactivated olefins from
readily available ICF2CO2Et reagent. This novel procedure
provided an efficient method for the construction of function-
alized fluoroalkylation 2,3-dihydrobenzofuran and indolin
derivatives in moderate to excellent yields. Remarkably, we have
3
realized anefficientconstruction ofCsp −CF2 andC−O/Nbonds
in a one-step manner through the straightforward conversion of
olefins, and the TEMPO−CF2CO2Et adduct was successfully
isolated. Further efforts into the mechanistic details as well as
explorations of medical applications of the products are currently
underway in our laboratory and will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.6b03865.
Typical experimental procedure, characterization for all
products (PDF)
Crystallographic data (CIF, CIF)
(11) (a) Uneyama, K.; Yanagiguchi, T.; Asai, H. Tetrahedron Lett. 1997,
38, 7763. (b) Ye, Z.; Gettys, K. E.; Shen, X.; Dai, M. Org. Lett. 2015, 17,
6074. (c)Xu,P.;Hu,K.;Gu, Z.;Cheng,Y.;Zhu,C. Chem.Commun.2015,
51, 7222. (d) Suh, C. W.; Kim, D. Y. Tetrahedron Lett. 2015, 56, 5661.
(12) Zhang, P.; Wolf, C. Angew. Chem., Int. Ed. 2013, 52, 7869.
(13) Yu, J.-S.; Liao, F.-M.; Gao, W.-M.; Liao, K.; Zuo, R.-L.; Zhou, J.
Angew. Chem., Int. Ed. 2015, 54, 7381.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: cewuwq@scut.edu.cn.
*E-mail: jianghf@scut.edu.cn.
ORCID
(14) Ma, G.; Wan, W.; Li, J.; Hu, Q.; Jiang, H.; Zhu, S.; Wang, J.; Hao, J.
Chem. Commun. 2014, 50, 9749.
Huanfeng Jiang: 0000-0002-4355-0294
Notes
(15)(a)Nguyen,J. D.;Tucker, J. W.;Konieczynska, M.D.;Stephenson,
C. R. J. J. Am. Chem. Soc. 2011, 133, 4160. (b) Wallentin, C. J.; Nguyen, J.
D.; Finkbeiner, P.;Stephenson, C. R. J. J. Am. Chem. Soc. 2012, 134, 8875.
(16) Zhang, Z.; Tang, X.; Thomoson, C. S.; Dolbier, W. R., Jr. Org. Lett.
2015, 17, 3528.
(17) (a) Zheng, M.; Chen, P.; Wu, W.; Jiang, H. Chem. Commun. 2016,
52, 84. (b) Liao, J.; Guo, W.; Zhang, Z.; Tang, X.; Wu, W.; Jiang, H. J. Org.
Chem. 2016, 81, 1304. (c) Huang, H.; Ji, X.; Wu, W.; Jiang, H. Chem. Soc.
Rev. 2015, 44, 1155. (d) Liao, J.; Zhang, Z.; Tang, X.; Wu, W.; Jiang, H. J.
Org. Chem. 2015, 80, 8903. (e) Zhang, Z.; Wu, W.; Liao, J.; Li, J.; Jiang, H.
Chem. - Eur. J. 2015, 21, 6708. (f) Wu, W.; Jiang, H. Acc. Chem. Res. 2014,
47, 2483. (g) Li, J.; Yang, W.; Yang, S.; Huang, L.; Wu, W.; Sun, Y.; Jiang,
H. Angew. Chem., Int. Ed. 2014, 53, 7219. (h)Wu, W.;Jiang, H. Acc. Chem.
Res. 2012, 45, 1736.
(18) CCDC 1503833 (3ae) contains the supplementary crystallo-
graphic data. These data can also be obtained free of charge from The
Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.
uk/data_request/cif.
(19) CCDC 1503834 (3bc) contains the supplementary crystallo-
graphic data. These data can also be obtained free of charge from The
Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.
uk/data_request/cif.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the National Key Research and Development
Program of China (2016YFA0602900), the National Natural
Science Foundation of China (21420102003), and the
Fundamental Research Funds for the Central Universities
(2015ZY001).
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