Selective difluoroalkylation of alkenes by using visible light photoredox catalysis

Article abstract of DOI:10.1039/c4cc05467a

A visible light-induced process for selective difluoroalkylation of unactivated alkenes has been developed. The choice of base is crucial for governing the chemoselectivity of the process to produce difluoroalkylated alkanes and alkenes. This journal is

Full text of DOI:10.1039/c4cc05467a

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Selective difluoroalkylation of alkenes by using
visible light photoredox catalysis†
Cite this: Chem. Commun., 2014,
0, 12884
5
Chunghyeon Yu, Naeem Iqbal, Sehyun Park and Eun Jin Cho*
Received 16th July 2014,
Accepted 30th August 2014
DOI: 10.1039/c4cc05467a
www.rsc.org/chemcomm
A visible light-induced process for selective difluoroalkylation of
unactivated alkenes has been developed. The choice of base is
crucial for governing the chemoselectivity of the process to produce
difluoroalkylated alkanes and alkenes.
Perfluoroalkylated organic compounds play significant roles in the
pharmaceutical, agrochemical and material sciences owing to the
substantial influence that fluorine substitution has on the physical
1
and chemical properties of substances. The incorporation of various
difluoroalkyl groups (–CF R) into organic compounds is particularly
2
interesting not only because these groups alter molecular properties,
but also because it introduces the possibility of functional group
modification of the appended alkyl groups. While significant
advances have been made in carrying out difluoro alkylation
2
reactions of arenes, similar transformations of alkenes are relatively
3
underdeveloped despite their potential importance [Fig. 1(1)].
In addition, many methods devised thus far for difluoro alkyla-
tion of alkenes have narrow scope and they require multi-step
prefunctionalization procedures.
Recent developments made in the studies of visible light
photoredox catalysis have attracted substantial attention because the
processes serve as environmentally friendly methods for promoting
4
selective radical reactions. Included in the group of new photoredox
Fig. 1 Difluoroalkylation reactions of alkenes.
catalyzed processes are radical mediated perfluoroalkylation
5
reactions of various organic substrates.
In the investigation described below, we have devised a new, process does not require prefunctionalization steps and proceeds
selective, photoredox catalyzed difluoroalkylation reaction of under mild environmentally benign conditions.
6
unactivated alkenes. The process is promoted by visible light
The mechanistic pathway followed in the difluoroalkylation
irradiation of a mixture of an alkene, ethyl 2-bromo-2,2-difluoro- reactions involves initial visible light photoredox catalyzed
acetate (BrCF CO Et) and bases in the presence of a photoredox formation of the CF radical, which adds to the alkene to form
catalyst [Fig. 1(2)]. The choice of base is crucial for guiding selective the CF -substituted alkyl radical intermediate 2. Depending on
2
2
2
2
formation of difluoro-alkene or -alkane products. Importantly, this the base present, intermediate 2 reacts by direct hydrogen atom
abstraction to produce alkane product 3 or by either bromine
6
abstraction from BrCF CO Et followed by HBr elimination or
2
2
Department of Bionanotechnology and Department of Applied Chemistry,
Hanyang University, Republic of Korea. E-mail: echo@hanyang.ac.kr;
Fax: +82-31-400-5457; Tel: +82-31-400-5496
oxidation of 2 followed by deprotonation to yield 6 [Fig. 1(2)].
In the initial phase of this effort, dodecene (1a) was used as a
2 2
model alkene and BrCF CO Et as the difluoroalkyl donor along
†
Electronic supplementary information (ESI) available: Experimental details and
NMR spectra. See DOI: 10.1039/c4cc05467a
with different bases, solvents, triscyclometalated ruthenium
1
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a
Table 1 Optimization of the conditions for the difluoroalkylation reaction of alkenes
b
Yield (%)
Entry
Photocatalyst (1 mol%)
Base (2 equiv.)
Solvent (0.1 M)
3a
4a
6a
1
2
3
4
5
6
7
8
9
[Ru(bpy)
[Ru(phen)
fac-[lr(dFppy)
3
]Cl
2
DBU
DBU
DBU
DBU
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
DMSO
THF
1,4-Dioxane
MeOH
DCM
DCM
DCM
DCM
MeCN
MeCN
1,4-Dioxane
DMF
30
25
35
55
40
—
59
41
—
—
—
—
39
99
Trace
Trace
—
Trace
8
3
—
—
—
—
—
—
(35 )
Trace
Trace
Trace
Trace
Trace
—
3
]Cl
2
3
]
fac-[lr(ppy)
fac-[lr(ppy)
fac-[lr(ppy)
fac-[lr(ppy)
fac-[lr(ppy)
fac-[lr(ppy)
fac-[lr(ppy)
fac-[lr(ppy)
fac-[lr(ppy)
fac-[lr(ppy)
fac-[lr(ppy)
—
fac-[lr(ppy)
fac-[lr(ppy)
fac-[lr(ppy)
fac-[lr(ppy)
3
]
3
]
3
]
3
]
3
]
3
]
3
]
3
]
3
]
TMEDA
K
2
CO
3
DBU/TMEDA (2eq : 2eq)
DBU/TMEDA (2eq : 2eq)
DBU/TMEDA (2eq : 2eq)
DBU/TMEDA (2eq : 2eq)
DBU/TMEDA (2eq : 2eq)
DBU/TMEDA (2eq : 2eq)
DBU/TMEDA (2eq : 2eq)
—
7
Trace
—
Trace
8
10
11
—
—
—
Trace
34
10
11
12
13
14
15
16
17
18
19
20
75
80
c
3
]
86
Trace
—
—
49
—
Trace
Trace
3
]
DBU/TMEDA (2eq : 2eq)
DBU/TMEDA (2eq : 2eq)
3
3
3
3
](no light)
]
]
]
K
2
K
2
K
2
K
2
CO
CO
CO
CO
3
3
3
3
/DBU (2eq : 2eq) d
; DBU (2eq : 2eq)d
; DBU (2eq : 2eq)
15
95(16 )
96(58 )
97(96 )
e
e
e
d
e
fac-[lr(ppy)
3
]
; DBU (2eq : 2eq)
—
a
b
19
Conditions: 1a (0.1 mmol), BrCF
2
CO
2
Et (0.15 mmol), 24 h. Yields were determined by using gas chromatography and F NMR spectroscopy
c
d
with internal standards dodecane and 4-fluorotoluene, respectively. CF
conversion of 1a to 4a. In parentheses are yields after 1 h reaction time.
2
CO
2
Me substituted alkane was formed. DBU was added after complete
e
and iridium photocatalysts, including [Ru(bpy) ]Cl , [Ru(phen) ]Cl , process, DBU acts solely as a base for the elimination reaction.
3
2
3
2
fac-[Ir(dFppy) ], and fac-[Ir(ppy) ], and visible light irradiation with Surprisingly, the use of DMF as solvent causes a decrease in time
3
3
blue LEDs (7 W) (Table 1). Interestingly, reactions using DBU in (1 h) needed to bring about complete conversion (entry 20).
MeCN were observed to generate only the difluoroalkane product The substrate scope of the difluoroalkylation process was
a despite incomplete alkene conversion (entries 1–4). Because examined next using the optimized conditions described above
fac-[Ir(ppy) ] displayed the highest reactivity it was used as the (Table 2). The results show that difluoroalkene forming reactions of
7
,8
3
3
photocatalyst in further optimization studies. The results showed a variety of aliphatic alkenes, containing a range of functional
that the nature of the base strongly influences the product distribu- groups including amide (3b, 3c, 3d), ester (3f, 3g), silyl ether (3e),
tion. For example, reaction of 1a employing TMEDA takes place to and aryl halide (3b, 3c), take place efficiently. Reaction of the amine
complete conversion to generate a mixture of difluroalkane 3a and substrate 1i generates the CF -containing lactam 3i owing to
2
bromodifluoroalkane 4a while that using K
bromodifluoroalkylated product 4a (entries 5 and 6). Importantly, a and ester moieties in the initially formed product (entry 9). In
reaction using a mixture of DBU and TMEDA as base takes place these processes, the alkenyl-CF CO Et product 6 together with 3 are
selectively to form 3a as the major product with complete conversion produced as minor products. Compared to those with terminal
2 3
CO produces only the intramolecular amide formation occurring between the amine
6
2
2
9
(
entry 7). Moreover, a change of the solvent to dichloromethane alkene substrates, reactions of internal alkenes take place more
increases the yield of 3a to 86% (entries 8–13). Reaction in MeOH slowly and generate mixtures of hydro- (3), bromo- (4), and alkenyl
also efficiently generates hydrodifluoroalkylation product 3a, which (6) products with different selectivities. Reactions of trans-5-decene
is then transformed into the CF CO Me substituted alkane by and cyclohexene are presented in Scheme S2 of the ESI.†
2
2
consecutive transesterification (entry 12).
Interestingly, reaction of an alkenyl-alcohol 1j generates a mixture
0
00
A further exploratory effort was carried out to uncover of difluoroalkylated products, 3j, 3j , and 3j (Scheme 1). In this
0
00
optimal conditions for production of the difluoroalkene pro- process, 3j and 3j are produced by consecutive nucleophilic
duct 6a. The finding that the use of K CO leads to quantitative acyl substitution reactions between the ester and hydroxyl
2
3
formation of the bromodifluoroalkane 4a (entry 6 in Table 1) groups in 3j. The ethoxy group acts as the leaving group in the
0
prompted the evaluation of a tandem process to generate 6a, in formation of lactone product 3j while ꢀCF
2
R is the leaving
1
0
00
which HBr elimination is carried out following difluoroalkylation. group in the generation of 3j .
Irradiation of a dichloromethane solution of fac-[Ir(ppy) ] in the The results of studies exploring the scope of the alkenyl-
and DBU produces both 3a difluoroalkylation process showed that both aliphatic and
and 6a due to the multiple roles played by DBU (entry 17). However, aromatic alkenes are suitable substrates for transformations
the addition of DBU to the reaction mixture after complete conver- that efficiently yield alkenyl-CF CO Et products 6 (Table 3).
sion of 1a to 4a leads to selective formation of 6a (entry 18). In this These reactions take place with excellent levels of regio- and
3
2 3
presence of 1a and a mixture of K CO
2
2
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a
a,b,c
Table 2 Hydrodifluoroalkylation reactions of aliphatic alkenes
Table 3 Alkenyl-difluoroalkylation reactions of alkenes
b
Yield
(%)
Ratioc
Entry
1
Product
(3 : 6)
d
3a
3b
85
4 : 1
2
3
70
75
11 : 1
3c
8 : 1
8 : 1
4
5
3d
3e
80
65
d
4 : 1
a
b
6
3f
90
5 : 1
Conditions: 1 (1.0 mmol), BrCFc
2
CO
2
Et (1.5 mmol), 2 h. Isolated yields
based on an average of two runs. The E/Z ratios were determined by using
gas chromatography and H NMR spectroscopy. Reactions proceed with-
out DBU addition (with 3 equiv. K CO and 5 h reaction time).
1
d
2
3
7
8
3g
3h
85
67
6 : 1
11 : 1
9
3i
70
7 : 1
a
b
2 2
Conditions: 1 (0.5 mmol), BrCF CO Et (0.75 mmol), 18–24 h. Isolated
c
yields based on an average of two runs. Ratios of 3 and 6 (alkenyl-
CF CO Et) were determined by using gas chromatography and F NMR
spectroscopy. Reactions on 40.5 mmol scales produce greater
amounts of 6 than those on a 0.1 mmol scale.
1
9
2 2
d
Fig. 2 Proposed mechanism for the difluoroalkylation reaction.
ꢁ
IV
+
2 2 3
produce the key intermediate CF CO Et, [Ir (ppy) ] and the
bromide ion. Addition of the electron deficient carbon-centered
ꢁ
radical CF CO Et to the alkene generates the difluoroalkylated
2
2
radical species 2, which participates in several reactions depending
on the base present. First, hydrodifluoroalkylated product 3 is
generated by direct hydrogen abstraction by 2 from amminium
Scheme 1 Reaction of alkenyl–alcohol 1j.
ꢁ
+
radical cations [NR
3
]
produced by one electron transfer from the
IV
+
3
corresponding tertiary amines to [Ir (ppy) ] [pathway (a) in Fig. 2].
E/Z stereoselectivity. Interestingly, electron rich styrene derivatives The direct H abstraction mechanism for conversion of 2 to 3 is
undergo alkenyl-difluoroalkylation to form 6p, 6q and 6r completely supported by the results of an experiment in which bromide 4a is
in the absence of DBU despite the need for longer reaction times.
subjected to the conditions used for the hydrodifluoroalkylation
Based on the results of the studies described above, it is reaction. In this process, only the alkene product 6a and not the
possible to propose the plausible mechanism outlined in Fig. 2 for debromonated product 3a is formed through E2 elimination
III
11
3
the processes. Photoexcitation of fac-[Ir (ppy) ] produces the metal- [Scheme 2].
IV
ꢁ
ꢀ
to-ligand charge-transfer excited state [Ir ppy (ppy)
2
], which is
Alternatively, alkenyl-difluoroalkyl product formation from 2
oxidatively quenched by single electron transfer to BrCF
2
CO Et to can take place by either pathway (b) or (c) shown in Fig. 2. In the
2
1
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7
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3
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ꢁ
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1
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IV
+
4
5
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3
(
(
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In the investigation described above, we have developed an
efficient and selective method for difluoroalkylation of alkenes.
Difluoroalkylated alkanes and alkenes are produced in these reac-
tions, which use ethyl 2-bromo-2,2-difluoroacetate as the difluoro-
alkyl donor, fac-Ir(ppy) as the photoredox catalyst and visible light
3
irradiation. The choice of base is crucial for governing the chemo-
selectivity of the process. For example, reactions in dichloromethane
(
3
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2
12
alkanes while those in DMF where K CO and DBU are bases
2
3
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2
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Notes and references
2 2
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1
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R act
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G. A. Olah, Angew. Chem., Int. Ed., 2012, 51, 12090; (c) Y. Fujiwara,
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(
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