Photoredox-Catalyzed Intramolecular Aminodifluoromethylation of Unactivated Alkenes

Article abstract of DOI:10.1021/acs.orglett.5b01616

A photoredox catalyzed aminodifluoromethylation of unactivated alkenes has been developed in which HCF₂SO₂Cl is used as the HCF₂ radical source. Sulfonamides were active nucleophiles in the final step of a tandem addition/oxidation/cyclization process to form pyrrolidines, and esters were found to cyclize to form lactones. Thus, a variety of pyrrolidines and lactones were obtained in moderate to excellent yield. In order for the cyclization reactions to be efficient, a combination of a copper catalyst (Cu(dap)₂Cl) and silver carbonate was crucial to suppressing a competing chloro, difluoroalkylation process.

Full text of DOI:10.1021/acs.orglett.5b01616

Letter
pubs.acs.org/OrgLett
Photoredox-Catalyzed Intramolecular Aminodifluoromethylation of
Unactivated Alkenes
Zuxiao Zhang, Xiaojun Tang, Charles S. Thomoson, and William R. Dolbier, Jr.*
Department of Chemistry, University of Florida, Gainesville, Florida 32611-7200, United States
S
* Supporting Information
ABSTRACT: A photoredox catalyzed aminodifluoromethylation
of unactivated alkenes has been developed in which HCF2SO2Cl
is used as the HCF2 radical source. Sulfonamides were active
nucleophiles in the final step of a tandem addition/oxidation/
cyclization process to form pyrrolidines, and esters were found to
cyclize to form lactones. Thus, a variety of pyrrolidines and lactones were obtained in moderate to excellent yield. In order for the
cyclization reactions to be efficient, a combination of a copper catalyst (Cu(dap)2Cl) and silver carbonate was crucial to
suppressing a competing chloro, difluoroalkylation process.
roperties of organic molecules, such as metabolic stability,
bioavailability, lipophilicity, and membrane permeability,
aromatic ring or form a carbon−chlorine bond through an
ATRA process (Scheme 1).12,13
P
play a crucial role in defining the efficacy of agrochemicals,
pharmaceuticals, and biomaterials.1 Among the commonly
encountered fluoroalkyl groups, difluoromethyl has drawn
increasing attention,2 in part because CF2H can act as a more
lipophilic hydrogen bond donor than typical donors such as
OH and NH.3 In addition, compared with CF3, the methods
available to introduce CF2H into organic compounds are
relatively limited.4 Recently much elegant difluoromethylation
work had been reported, which mainly focused on constructing
difluoromethyl arenes and heteroarenes.5 Nonaromatic hetero-
cycles such as pyrrolidine are also of synthetic interest, such
structures being present in a wide variety of naturally occurring
and biologically active molecules.6 As a result the development
of efficient methods for the incorporation of CF2H into
pyrrolidines is a subject worthy of attention.
Recently numerous papers reporting methods of difunction-
alization of alkenes have appeared.7 In addition, intramolecular
difunctionalizations of olefins, including aminohalogenation,
carboamination, and oxyamination, have offered an efficient
strategy for the introduction of various functional groups while
constructing such heterocycles.8 Aminofluorinations have also
been realized.9 Regarding fluoroalkylations, Buchwald’s group
reported in 2012 the oxytrifluoromethylation of unactivated
alkenes using Togni’s reagent combined with a copper
catalyst.10 In 2014 Liu’s group, using a similar strategy, was
successful in observing aminotrifluoromethylation.11
Scheme 1. Photoredox Catalyzed Difluoromethylation
Reactions
In this paper, we wish to report a photoredox catalyzed
intramolecular aminodifluoromethylation of unactivated al-
kenes under mild conditions. In designing this study our
hypothesis was that the CF2H radical should initially react with
alkenes to form an alkyl radical, which can then be oxidized by
the catalyst to form a carbocation, which can then itself be
trapped intramolecularly by a not readily oxidizable nucleo-
phile, such as the nitrogen of a sulfonamide to produce a
difluoromethylated pyrrolidine, as shown in the mechanistic
scheme below (Scheme 2).
Scheme 2. Probable Mechanism
With the lack of a good electrophilic difluoromethylation
reagent, it has remained a challenge to carry out difluor-
omethylations in a similar manner. However, our research
group has recently focused efforts on the use of fluoroalkyl-
sulfonyl chlorides for the purpose of introduction of fluoroalkyl
groups, via initial alkene addition. In particular, the CF2H
radical generated from single electron reduction of CF2HSO2Cl
by a photoredox catalyst has been shown to have excellent
reactivity toward electron-deficient alkenes. The radical formed
by such additions could either undergo cyclization with an
Received: June 2, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01616
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
To test our hypothesis we chose sulfonamide 1a as a model
substrate that could be used to optimize reaction conditions
(Table 1). Initially, for the reaction with CF2HSO2Cl,
Scheme 3. Substrate Scope
a
Table 1. Optimization of Reaction Conditions
b
entry
cat.
base
temp/°C
yield
c
1
1 mol % Ir(ppy)3
Na2CO3
K2HPO4
Ag2CO3
Cs2CO3
Na2CO3
K2CO3
rt
ND (26%)
ND (60%)
ND (59%)
ND
c
2
1 mol % Ir(ppy)3
rt
c
3
1 mol % Ir(ppy)3
rt
c
4
1 mol % Ir(ppy)3
rt
5
0.75 mol % Cu(dap)2Cl
0.75 mol % Cu(dap)2Cl
0.75 mol % Cu(dap)2Cl
0.75 mol % Cu(dap)2Cl
0.75 mol % Cu(dap)2Cl
0.75 mol % Cu(dap)2Cl
0.75 mol % Cu(dap)2Cl
0.75 mol % Cu(dap)2Cl
1 mol % Cu(dap)2Cl
0.3 mol % Cu(dap)2Cl
90
90
90
90
90
90
90
100
70
70
28% (33%)
9% (11%)
ND
6
7
Cs2CO3
K2HPO4
K3PO4
8
19% (20%)
33% (39%)
28% (31%)
14% (16%)
50% (trace)
76% (trace)
51% (trace)
9
10
11
12
13
14
NaOAc
KOAc
Ag2CO3
Ag2CO3
Ag2CO3
a
Reactions were run with 0.1 mmol of 1a, 0.2 mmol of CF2HSO2Cl,
0.2 mmol of base, and 0.0001 mmol of catalyst in 1 mL of DCE. All
yields were based on 1a using CF3CON(Me)2 as the internal standard.
b
Values in parentheses are yields of chloro, difluoromethylation
c
addition products. CH3CN as solvent.
IrIII(ppy)3 was tried as the catalyst in CH3CN as solvent,
using various bases under visible light (entries 1−4).
Unfortunately only the chloro, difluoromethylation (addition)
product was detected, instead of cyclization, which suggested
that IrIV(ppy)3Cl could not oxidize the carbon radical
intermediate efficiently. In the absence of oxidation, the carbon
radical abstracted the chlorine atom from CF2HSO2Cl to
propagate the simple addition reaction. Several reports indicate
that copper catalysts can be superior to Ir(ppy)3 for this
oxidation step. Therefore, it was decided to examine Cu-
(dap)2Cl as the photoredox catalyst. Even though this catalyst
has a lower oxidation potential compared with Ir(ppy)3,14 it
had earlier been shown to be efficient in the reductive step to
generate the CF2H radical from HCF2SO2Cl.
Whereas, no cyclization had been observed when using the Ir
catalyst, 28% of the cyclization product was observed along
with 33% of the addition product in the initial experiment using
Cu(dap)2Cl in DCE with NaCO3 as the base at 90 °C (entry
5). To improve the yield and to suppress the chlorine addition
product, Ag2CO3 was added to the reaction (entry 13), and as a
result only trace amounts of the chlorine addition product was
observed, and the reaction gave the desired 2a as the major
product in 50% yield. Finally by lowering the temperature and
increasing the amount of catalyst to 1 mol %, the reaction
displayed good chemoselectivity, giving a single product 2a in
76% yield (entry 14).
a
Reactions were run with 0.2 mmol of 1a, 0.4 mmol of CF2HSO2Cl,
0.4 mmol of base, and 0.0002 mmol of catalyst in 2 mL of solvent.
b
Isolated yield.
observable cyclization. Also, carboxamides, such as Boc (1d)
and acetamide (1e), were ineffective substrates.
Then other substrates with gem-substituents (1f and 1g)
were tested, with these reactions also proceeding smoothly to
provide product 2f and 2g in good yield. When a substituent
was introduced to the position α to nitrogen, the yield of the
product (2h) was lowered slightly. Monosubstituted sub-
stituents or those without gem-substituents substrates 1i−1l
were also compatible with the reaction conditions, delivering
products 2i−2l in moderate to good yield. Furthermore, both
cis- and trans-cyclohexyl substrates 1m and 1n proceeded very
well to provide products 2m and 2n in excellent yield, as a
mixture of diastereomers. However, a substrate with gem-
diphenyl substituents (1o) proved to be a reluctant reactant,
with only 20% of product being obtained.
Using this optimized protocol, the substrate scope was
examined (Scheme 3). The protecting group on nitrogen
proved to have a significant effect upon its efficacy in the
reaction. It was found that p-methoxybenzene-sulfonamide
(1b) was a slightly better substrate, but that the more electron-
deficient p-nitrobenzenesulfonamide (nosyl) substrate gave no
To our surprise, when substrates with gem-diester sub-
stituents 1p and 1q were examined, the lactone products 2p
and 2q were isolated instead of the expected pyrrolidine. This
seemed to indicate that ester carbonyls are better nucleophiles
in the reaction than a sulfonamide nitrogen. Consistent with
B
DOI: 10.1021/acs.orglett.5b01616
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
this supposition, ester 1r was an excellent substrate, producing
lactone (2r) in excellent yield.
Since the chlorine addition product had been a significant
side product in the absence of AgCO3, a stepwise process was
considered to be a mechanistic possibility. When the chlorine
addition product (3g) was synthesized (Scheme 4) and then
catalyzed intramolecular amino- and oxy-difluoromethylation
reactions of unactivated alkenes. In order for the cyclization
reactions to be efficient, a copper catalyst (Cu(dap)2Cl) in
combination with silver carbonate was crucial to suppressing
the competing chloro, difluoroalkylation process. Using this
procedure, a variety of pyrrolidines could be efficiently
synthesized in moderate to excellent yield. Esters exhibited
even greater nucleophilic reactivity to prepare lactones in very
good yield.
Scheme 4. Probe of Mechanism
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization and NMR spectra of
new compounds. The Supporting Information is available free
of charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01616.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: wrd@chem.ufl.edu.
Notes
treated with 2.0 equiv of silver carbonate under the same
reaction conditions, only 16% of the cyclization product was
formed, with 77% of the starting material remaining. However,
when 1 mol % Cu(dap)2Cl was added to the reaction mixture,
conversion of 3g was complete. What all of this indicates is that,
under the optimized conditions, either pathway (one or two
step) to eventual cyclized product can be effective, and the two
pathways are likely competing.
Sometimes using a clear two-step procedure may be
preferred over the “one pot” method. For example, when the
two-step procedure was used for gem-diphenyl substrate 1o,
product 2o was obtained in a significantly higher overall yield
than when the one-pot procedure was used (Scheme 5).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support of this research by a grant from Syngenta Crop
Protection is gratefully acknowledged.
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