Halogen-Bond-Promoted Photoactivation of Perfluoroalkyl Iodides: A Photochemical Protocol for Perfluoroalkylation Reactions

Article abstract of DOI:10.1021/acs.orglett.7b00375

A new protocol for photochemical perfluoroalkylation reactions using perfluoroalkyl iodide, amine additive, and THF solvent is reported. This protocol does not require a photoredox catalyst and proceeds at ambient temperature with irradiation from a compact fluorescent lamp, low-intensity UV lamp, or sunlight. This protocol can be applied to the synthesis of perfluoroalkyl-substituted phenanthridines as well as effect the iodo-perfluoroalkylation of alkenes/alkynes and the C-H perfluoroalkylation of electron-rich arenes and heteroarenes. This C-H perfluoroalkylation reaction offers a unique method for site-selective labeling of oligopeptides at the tryptophan residue.

Full text of DOI:10.1021/acs.orglett.7b00375

Letter
pubs.acs.org/OrgLett
Halogen-Bond-Promoted Photoactivation of Perfluoroalkyl Iodides:
A Photochemical Protocol for Perfluoroalkylation Reactions
Yaxin Wang,† Junhua Wang,† Guo-Xing Li,† Gang He,† and Gong Chen*,†,‡
†State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin), Nankai University, Tianjin 300071, China
‡Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
S
* Supporting Information
ABSTRACT: A new protocol for photochemical perfluor-
oalkylation reactions using perfluoroalkyl iodide, amine
additive, and THF solvent is reported. This protocol does
not require a photoredox catalyst and proceeds at ambient
temperature with irradiation from a compact fluorescent lamp,
low-intensity UV lamp, or sunlight. This protocol can be
applied to the synthesis of perfluoroalkyl-substituted phenan-
thridines as well as effect the iodo-perfluoroalkylation of
alkenes/alkynes and the C−H perfluoroalkylation of electron-
rich arenes and heteroarenes. This C−H perfluoroalkylation reaction offers a unique method for site-selective labeling of
oligopeptides at the tryptophan residue.
espite recent advances, more efficient, practical, econom-
and co-workers describing the synthesis of 6-perfluoroalkylated
Dical, and environmentally friendly perfluoroalkylation phenanthridines from 2-isocyanobiphenyls and perfluoroalkyl
iodides via a radical cascade process (Scheme 1).12a Studer
methods remain in demand for applications in pharmaceutical,
agrochemical, and materials science.1,2 Reactions of electro-
proposed that perfluoroalkyl radicals generated from the
corresponding halides first add to the isocyanide, forming an
imidoyl radical.12−14 This imidoyl radical then undergoes an
intramolecular addition reaction with the nearby phenyl ring at
the ortho position, forming a cyclohexadienyl radical. This
cyclohexadienyl radical is deprotonated, and reaction with
perfluoroalkyl halide via single-electron transfer propagates the
radical chain and provides phenanthridine product. Studer’s
optimized conditions for the reaction of 1 and 2 require 1.5
equiv of Cs2CO3 in dioxane at 110 °C.12a Other alkali metal
bases such as K2CO3 and Na2CO3 were ineffective, and the role
of Cs2CO3 was unclear. Intrigued, we began to investigate of
the role of base in this reaction system. We found that the
reaction proceeds to a small degree (∼10% yield of 3) in the
absence of Cs2CO3 when conducted at 30 °C under irradiation
from a household 25 W compact fluorescent lamp (CFL) in
THF solvent (see the Supporting Information for details). No
product 3 was formed when the reaction was performed in the
dark. We were pleased to find that addition of 1.5 equiv of Et3N
provided 3 in 64% yield in THF. Tetrahydropyran (THP) or 2-
MeTHF solvent gave better results than dioxane, CHCl3, or
CH3CN. Interestingly, reactions performed with irradiation
from a Hg UV lamp of the same power intensity (25 W, 254
nm), and reactions performed with sunlight, gave comparable
yields. Under UV irradiation but without Et3N, the reaction
gave poor yield.
philic perfluoroalkyl radicals generated from readily accessible
perfluoroalkyl halide (Rf−X) precursors have offered a versatile
means to incorporate various perfluoroalkyl groups into
different unsaturated substrates.3−11 For environmental and
practical reasons, radical perfluoroalkylation methods employ-
ing photochemical radical initiation are preferable to those
using reactive organic reagents such as azos, peroxides, and
various metal catalysts. The addition reactions of perfluoroalkyl
halides with alkenes and alkynes under high-intensity UV
irradiation have been well studied.4 Recently, more operation-
ally convenient perfluoroalkylation methods have become
available based on photoredox catalysis manifolds.5,7,9a
Perfluoroalkylation reactions that do not require photocatalyst
represent a further stage of development. Activation of
perfluoroalkyl halides through photoactive electron donor−
acceptor (EDA) complexes have been employed for the visible-
light-mediated perfluoroalkylation of β-ketoesters and arenes.10
Recently, Yu reported a halogen-bond-promoted activation of
Rf−I’s under visible-light irradiation (VL from LED lamp) for
synthesis of quinoxalines from o-diisocyanoarenes using a
Bn2NH promoter in CH3CN solvent.11 Herein, we report a
new photochemical protocol for perfluoroalkylation that
requires perfluoroalkyl iodide, N,N,N′,N′-tetraethylethylenedi-
amine (TEEDA) additive, THF solvent, and a light source,
which may be a compact fluorescent lamp, a low-intensity UV
lamp, or sunlight.
Our interest in exploring perfluoroalkylation reactions using
perfluoroalkyl halides was prompted by a report from Studer
Received: February 6, 2017
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.7b00375
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Organic Letters
Letter
Scheme 1. Evaluation of Amine Promoters for Synthesis of
Phenanthridine 3 from 1 and C4F9−I under CFL
Irradiation*
Scheme 2. Substrate Scope of Phenanthridine Synthesis*
*
Isolated yield on 0.2 mmol scale under the standard CFL irradiation
a
conditions. Excess of CF3I was used (sparging THF solution with
CF3I gas; see the Supporting Information). 5 equiv of bromide and 3
b
equiv of TEEDA were used.
*
CFL: 25 W. UV (254 nm): low-pressure Hg vapor lamp, 25 W.
Sunlight: direct irradiation for 4 h. Yields are based on 1H NMR
analysis of the crude reaction mixture on a 0.2 mmol scale performed
in a 4 mL borosilicate glass vial under Ar. Isolated yield on 0.2 mmol
As shown in Scheme 3A, perfluoroalkyl halides can undergo
1,2-addition reactions with terminal alkenes to give iodo-
perfluoroalkylated products with excellent regioselectivity
under our standard conditions with CFL irradiation.4,5
Functional groups such as PhthN, benzoate ester, phenyl
ether, and ketone are tolerated. Notably, subjecting quinine,
which contains hydroxyl and pyridine moieties, to the reaction
provided 24 in good yield and selectivity. As seen in 19, the
reaction performed well with irradiation from either a low-
intensity UV lamp or sunlight. As shown in Scheme 3B,
perfluoroalkyl halides react with terminal alkynes to give iodo-
perfluoroalkylation products in good yield and excellent
regioselectivity. Perfluoroalkyl radicals generated via the
photochemical activation of perfluoroalkyl halides likely add
to the alkene or alkyne substrate to form a secondary alkyl or
vinyl radical intermediate. The resulting radical could then
abstract an I atom from a perfluoroalkyl iodide molecule to give
difunctionalized product and propagate the radical chain.14
The C−H perfluoroalkylation of electron-rich arenes and
heteroarenes with perfluoroalkyl iodides has been achieved
using several different radical initiation systems.6,7 As shown in
Scheme 4, reactions of electron-rich arenes such as aniline and
heteroarenes such as pyrrole using our standard method
provided perfluoroalkylated products in moderate yield (27−
29). 3-Methylindole was subjected to reaction with perfluor-
oalkyl iodides of varied chain lengths, providing C2-
perfluoroalkylated products 30−32 in good to excellent yield.
The same reaction using a 25 W Hg UV lamp or sunlight gave
similar results (see 32). As seen in 33 and Trp 34, unprotected
a
b
scale. Isolated yield on 1 mmol scale.
Next, we examined the performance of other organic bases as
additives in the photochemical reaction of 1 and 2 under CFL
irradiation (25 W) in THF solvent. A variety of amines
promote the reaction. In general, tertiary amines are slightly
more effective than secondary and primary amines (see EtNH2,
Et2NH, and Et3N). Electron-rich amines give better results than
electron-deficient amines (see N-ethylpiperidine vs N-ethyl-
morpholine). Pyridines are ineffective. N,N,N′,N′-Tetraethyle-
thylenediamine (TEEDA) was the most effective additive,
providing 3 in 91% isolated yield after 36 h of CFL irradition.15
With TEEDA additive, the reaction also gave excellent yields
under irradiation from a low-intensity Hg UV lamp (254 nm,
25 W) or sunlight.
The scope of the phenanthridine synthesis was explored
under the optimized conditions with TEEDA additive and CFL
irradiation (Scheme 2). As seen in 4−6, 2-isocyanobiphenyls
bearing various substitution patterns can react with C4F9−I 2 in
good to excellent yield and regioselectivity. An isocyanide
substrate containing a pyridine ring was tolerated (see 7). As
shown in 10−15, linear and branched perfluoroalkyl iodides of
various lengths provided excellent results. α-Bromoacetates
bearing one or two α-substituents also provide phenanthridine
product in good yield under slightly modified conditions (16−
18).
B
DOI: 10.1021/acs.orglett.7b00375
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Organic Letters
Letter
Scheme 3. Addition of Perfluoroalkyl Iodide to Alkenes and
Alkynes*
Scheme 4. C−H Perfluoroalkylation of Electron-Rich Arene
and Heteroarenes*
*
Isolated yield on 0.2 mmol scale under the standard CFL irradiation
a
conditions. The other regioisomers were not observed in 19F NMR
analysis of the crude reaction mixture. UV(254 nm): low-pressure Hg
b
vapor lamp, 25 W.
*
NH2 and CO2H groups were tolerated. Furthermore, we were
delighted to find that tryptophan (Trp) containing short
peptides can be perfluoroalkylated at the C2 position of the Trp
residue in good yield and excellent selectivity under the
standard reaction conditions. This reaction offers a valuable
orthogonal strategy for peptide labeling based on underex-
plored Trp chemistry.
Isolated yield on 0.2 mmol scale under the standard CFL irradiation
a
b
conditions. RSM: recovered starting material. UV(254 nm): low-
pressure Hg vapor UV lamp, 25 W. Isolated as a Bn ester after
treatment with BnBr. Isolated as a Nα-Boc-protected product after
treatment with Boc2O. 0.1 mmol scale, 10 equiv of Rf−I, and 6 equiv
of TEEDA were used.
c
d
e
Perfluoroalkyl iodides can form halogen bond (XB)
complexes/adducts with Lewis bases (LB) such as amines.16−19
In these adducts, the amine, designated as the acceptor in the
XB complex, uses its lone-pair electrons to interact with the σ*
antibonding orbital of the C−I bond of perfluoroalkyl iodides
(designated as XB donor). Using an 19F NMR titration method
and a Job’s plot analysis, we observed formation of the 1:1
complex between NEt3 and C10F21−I with a binding constant
Ka of 0.72 M−1 in CHCl3 (see the Supporting Information for
details).11,20 TEEDA and C10F21−I form a 1:1 complex with a
slightly higher Ka (1.1 M−1). Interestingly, THF and C10F21−I
also form a 1:1 complex with a Ka of 0.28 M−1 in CHCl3. A
smaller Ka of 0.17 M−1 was observed for dioxane and C10F21−I,
likely due to its additional electron-withdrawing O atom.
Choice of light source clearly has an impact on the yield of
reaction of 1 and 2 (see the Supporting Information for
details). Irradiation by red, yellow, or green LEDs (25W) gave
little product 3. However, a blue LED (25W) gave 21% yield,
while a purple LED (25W) gave 57% yield. Irradiation with a
UV lamp (254 or 365 nm), a CFL of the same power intensity,
or sunlight gave excellent yields. It is known that CFLs emit a
small amount of UV light. Taken together, these results suggest
that low-intensity irradiation in the UV region is responsible for
the observed halogen bonding promoted photochemical
reactivity of perfluoroalkyl iodides.
In summary, we have developed a simple, mild, and efficient
protocol for photochemical perfluoroalkylation reactions using
inexpensive perfluoroalkyl iodides, amine additive, and THF
solvent. This protocol does not require photoredox catalyst and
takes place under the irradiation of a compact fluorescent lamp,
low-intensity UV lamp, or sunlight at ambient temperature.
This protocol can be applied to the synthesis of perfluoroalkyl-
substituted phenanthridines, to addition reactions of alkenes/
alkynes, and the C−H perfluoroalkylation of electron-rich
arenes and heteroarenes. This protocol can be used for C−H
perfluoroalkylation of Trp, offering a unique method for site-
selective labeling of oligopeptides. Mechanistic studies suggest
that halogen-bond interactions between perfluoroalkyl iodides
and amine and THF solvent promote the photochemical
C
DOI: 10.1021/acs.orglett.7b00375
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Organic Letters
Letter
2005. (b) Straathof, N. J. W.; Gemoets, H. P. L.; Wang, X.; Schouten,
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ASSOCIATED CONTENT
* Supporting Information
■
S
(9) (a) Nagib, D. A.; Scott, M. K.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2009, 131, 10875. (b) Pham, P. V.; Nagib, D. A.; MacMillan, D.
W. C. Angew. Chem., Int. Ed. 2011, 50, 6119.
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Ed. 2014, 53, 4921. (b) Wozniak, L.; Murphy, J. J.; Melchiorre, P. J.
Am. Chem. Soc. 2015, 137, 5678.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00375.
Additional experimental procedures and spectroscopic
data for all new compounds (PDF)
(11) Sun, X.; Wang, W.; Li, Y.; Ma, J.; Yu, S. Org. Lett. 2016, 18,
4638.
(12) (a) Zhang, B.; Studer, A. Org. Lett. 2014, 16, 3990. (b) Zhang,
B.; Studer, A. Chem. Soc. Rev. 2015, 44, 3505.
AUTHOR INFORMATION
■
(13) For other selected examples, see: (a) Nanni, D.; Pareschi, P.;
Rizzoli, C.; Sgarabotto, P.; Tundo, T. Tetrahedron 1995, 51, 9045.
(b) Tobisu, M.; Koh, K.; Furukawa, T.; Chatani, N. Angew. Chem., Int.
Corresponding Author
*E-mail: gongchen@nankai.edu.cn, guc11@psu.edu.
ORCID
Ed. 2012, 51, 11363. (c) Zhang, B.; Muck-Lichtenfeld, C.; Daniliuc, C.
̈
G.; Studer, A. Angew. Chem., Int. Ed. 2013, 52, 10792. (d) Jiang, H.;
Cheng, Y.; Wang, R.; Zheng, M.; Zhang, Y.; Yu, S. Angew. Chem., Int.
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Lett. 2013, 15, 5520. (h) He, Z.; Bae, M.; Wu, J.; Jamison, T. F. Angew.
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Gong Chen: 0000-0002-5067-9889
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank the State Key Laboratory of Elemento-Organic
Chemistry at Nankai University for financial support of this
work.
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