Visible Light-Induced Radical Iodoperfluoroalkylation of Unactivated Olefins Cooperatively Catalyzed by Enamines and Amines

Article abstract of DOI:10.1002/ejoc.201901896

Fluoro-organic compounds feature prominently in functional materials and in the pharmaceutical and agrochemical industries. Herein, we report a visible light-induced atom transfer radical addition of perfluoroalkyl iodide to alkenes/alkynes in the presenc

Full text of DOI:10.1002/ejoc.201901896

A Journal of
Accepted Article
Title: Visible Light-Induced Radical Iodoperfluoroalkylation of
Unactivated Olefins Cooperatively Catalyzed by Enamines and
Amines
Authors: Tomoko Yajima, Mao Murase, and Yu Ofuji
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901896
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10.1002/ejoc.201901896
European Journal of Organic Chemistry
COMMUNICATION
Visible Light-Induced Radical Iodoperfluoroalkylation of
Unactivated Olefins Cooperatively Catalyzed by Enamines and
Amines
Tomoko Yajima*[a], Mao Murase[a] and Yu Ofuji[a]
[a]
Prof. Dr. T. Yajima, 0000-0001-5188-7412, M. Murase, Y. Ofuji
Department of Chemistry
Ochanomizu University
2-1-1 Otuska, Bunkyo-ku, Tokyo 112-8610 (Japan)
E-mail: yajima.tomoko@ocha.ac.jp
http://www.sci.ocha.ac.jp/chemHP/labos/yajimaHP/top.html
Supporting information for this article is given via a link at the end of the document.
Abstract: Fluoro-organic compounds feature prominently in
functional materials and in the pharmaceutical and agrochemical
industries. Herein, we report a visible light-induced atom transfer
radical addition of perfluoroalkyl iodide to alkenes/alkynes in the
presence of aldehydes and amines. The metal-free process requires
mild reaction conditions and enables iodoperfluoroalkylation. The
reaction proceeds via the cooperative action of an enamine and amine.
as a photo redox catalyst. Hence, we investigated the photo-
induced ATRA of perfluoroalkyl iodide in the presence of amines
and aldehydes.
Previous Work: Perfluoroalkylaionof enamine
RfI
R1
O
N
O
N
R1
H
R1
R2
H
RfI
+
H
H
R2
R2
Rf
Fluoro-organic compounds are among the most abundant motifs
in the pharmaceutical and agrochemical industries and in
functional materials.[1] In response to increasing demands for
such materials in these fields, a number of mild fluoroalkylation
EDA Complex
Intermediate
This Work: Enamine catalyzed iodoperfluoroalkylation
RfI
R1
N
N
methods have been reported.[2] Atom transfer radical addition
H
Rf
I
RfI
+
O
[3]
H
R
(ATRA)
of perfluoroalkyl iodides with alkenes has received
R1
R2
R
H
significant attention as one of the most direct and convenient
methods for the synthesis of such compounds. Advantageously,
a variety of perfluoroalkyl iodides are commercially available.[4]
ATRA, which can generate new C–C and C–X bonds (X =
halogen) simultaneously, is an atom-economical and effective
process for functionalizing olefinic substrates. Thus, the use of
perfluoroalkyl iodide can provide a general protocol for the
introduction of a diverse range of perfluoroalkyl groups.
R2
EDA Complex
Catalyst
Scheme 1. Enamine assisted visible light-induced perfluoroalkylation.
The reaction between decene and a perfluoroalkyl iodide was
chosen as a model reaction of ATRA (Table 1). Based on our
previous report, decene was reacted with 2.0 equiv of
perfluorohexyl iodide in CH2Cl2 in the presence of 2.1 equiv
pyrrolidine and 1 equiv aldehyde 1a for 16 h, irradiated with a 23
W CFL under Ar atmosphere (entry 1).[10] The corresponding
iodoperfluorohexyl product 3a was obtained in 40% yield,
together with 47% perfluoroalkylated aldehyde 4. Then, the
amounts of both 1a and the amine were reduced to 10 mol%
(entry 2). The yield of the desired product increased to 66%, while
that of the side product decreased. Next, aldehydes 1b–1d were
examined in the reaction, and diphenylacetaldehyde (1d) was
found to give optimal results (entries 3–5), and the
iodoperfluoroalkylation proceeded cleanly and smoothly (Table
S1). The choice of amine dramatically affected the yield, with
pyrrolidine being the most suitable for this reaction (entries 6–8).
The equivalents of both the aldehyde and amine were reduced,
and it was found that 1 mol% of each reactant was sufficient for
the reaction to proceed (entries 9 and 10). The effect of various
light sources was also investigated (entries 11–13). When a green
LED (λmax = 525 nm) was employed, the yield decreased to 89%,
The ATRA using perfluoroalkyl iodide under UV irradiation and
thermal conditions has been successfully developed. [5] In recent
years, photo redox metal-[6] and nonmetal-catalyzed,[7] or
sensitizer-catalyzed[8] reactions have been suggested as
sustainable and expedient protocols for achieving such
transformations.
More
recently,
visible
light-induced
iodoperfluoroalkylation reactions driven by electron donor-
acceptor (EDA) complexes have attracted much attention.[9] Small,
readily available organic molecules such as amines, phenoxides,
and phosphines can activate perfluoroalkyl iodides under visible
light irradiation and function as photocatalysts. Because these
reactions are mild, sustainable, and efficient, discovery of novel
effective activation molecules that are active at low catalytic
amounts will expand their utility.
We have previously reported the visible light-induced
[10]
perfluoroalkylation of aldehydes via enamines (Scheme 1).
The reaction proceeds via the formation of an electron donor-
acceptor (EDA) complex[11] of perfluoroalkyl iodide and an
enamine. As the reaction can effectively generate the
perfluoroalkyl radical, we focused on the potential of the enamine
1
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10.1002/ejoc.201901896
European Journal of Organic Chemistry
COMMUNICATION
while blue (λmax = 470 nm) or white LEDs led to excellent yields.
No reaction occurred in the dark (entry 14), or in the absence of
either aldehyde or amine (entries 15 and 16). When the reaction
of ethyl iododifluoroacetate, which afforded a moderate yield
(entry 6). When IC2F4OC2F4Br was employed, bromination of 2
did not occur (entry 7), indicating that the reaction is selective for
the iodide.
was performed with
1 mol% N-methylpyrrolidine, without
aldehyde (entry 17), it did not proceed, indicating that the -ene
component of the enamine was important. Similarly, the reaction
did not proceed when triethylamine was employed in the absence
of aldehyde (entry 18). Hence, the amine on its own was not an
effective photocatalyst under our reaction conditions.
Table 2. Screening of Perfluoroalkyl Iodides[a]
1d
(10 mol%)
Rf
I
pyrrolidine (10 mol%)
Thus, it was concluded that light, aldehydes, and amines were all
essential components for this reaction.
RfI
+
C8H17
CH2Cl2, r.t., 16 h
23 W CFL
C8H17
3b-h
(1.1 eq)
2
Table 1. Screening of aldehydes and amines[a]
Entry
RfI
Product
3b
Yield (%)
1
2
3
4
5
6
7
CF3I
98
92
99
98
95
40
95
: R1 = Bn, R2 = Me
O
1a
1b: R1 = Bn, R2 = H
R1
O
: R1 = Ph, R2 = Me
H
C3F7I
i-C3F7I
C4F9I
3c
C F
1c
6
13
Bn
: R1 = R2 = Ph
1d
R2
+
H
+ C6F13
(1.1 eq)
I
3d
C8H17
C6F13
I
C8H17
amine, CH2Cl2
r.t., 16 h
23 W CFL
3a
4
2
3e
C7F15
I
3f
Entry
1
1 (equiv)
1a (1.0)
1a (0.1)
1b (0.1)
1c (0.1)
1d (0.1)
1d (0.1)
1d (0.1)
1d (0.1)
1d (0.05)
1d (0.01)
1d (0.1)
1d (0.1)
1d (0.1)
1d (0.1)
-
Amine (equiv)
Yield 3a (%)
40[b]
66
ICF2CO2Et
3g
pyrrolidine (2.1)
pyrrolidine (0.1)
pyrrolidine (0.1)
pyrrolidine (0.1)
pyrrolidine (0.1)
piperidine (0.1)
i-Pr2NH (0.1)
IC2F4OC2F4Br
3h
2
[a] Reaction conditions: 2 (0.75 mmol), perfluoroalkyl iodide (1.1 equiv), 1d (0.1
equiv) and pyrrolidine (0.1 equiv) in CH2Cl2 (7.5 mL), irradiation using 23 W CFL
for 16 h under Ar atmosphere.
3
62
4
91
5
99
Next, the iodoperfluorohexylation of a series of unactivated
alkenes and alkynes was investigated (Scheme 2). The substrate
bearing an unprotected alcohol afforded 6a in good yield. This
was in contrast to the low yield obtained in the visible light-induced
perfluoroalkylation using eosin Y as a catalyst, as reported in our
previous study.[7b] The ester- 5d, amide- 5e, and benzyl- 5b
containing substrates gave the respective products in moderate
to excellent yields. The reaction likewise proceeded with 1,1-
disubstituted olefin 5c and internal olefins 5f–5i, whilst no reaction
took place with cyclohexene. The reaction proceeded with decyne
(5j) to give 6j in a low yield as an E/Z mixture. However, alkyne
6
trace
n.r.
n.r.
94
7
8
i-Pr2NEt (0.1)
pyrrolidine (0.05)
pyrrolidine (0.01)
pyrrolidine (0.1)
pyrrolidine (0.1)
pyrrolidine (0.1)
pyrrolidine (0.1)
pyrrolidine (0.1)
-
9
10
11[c]
12[d]
13[e]
14[f]
15
16
17
18
96
89
94
5k bearing
a hydroxyl group gave 6k in good yield.
99
Phenylacetylene afforded the corresponding product in 34% yield.
The use of excess aldehyde and amine did, however, significantly
improve the yield of alkynes.
n.r.
n.r.
n.r.
n.r.
n.r.
1d (0.1)
-
N-Methylpyrrolidine (0.01)
-
Et3N (0.01)
[a] Reaction conditions: 2 (0.75 mmol), C6F13I (1.1 equiv) in CH2Cl2 (7.5 mL),
irradiation using 23 W CFL for 16 h under Ar atmosphere, unless otherwise
stated. [b] 47% 4 was also observed. [c] Green LED was used instead of CFL.
[d] Blue LED was used instead of CFL. [e] White LED was used instead of CFL.
[f] Reaction was performed in the absence of light.
Next, we investigated the scope of perfluoroalkyl iodides (Table
2) with the optimized reaction conditions (Table 1, Entry 5). A wide
range of perfluoroalkyl reagents afforded the corresponding
iodoperfluoroalkylated products in good yield, with the exception
2
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10.1002/ejoc.201901896
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COMMUNICATION
Table 3. Reaction using synthesized enamine[a]
R1 C6F13
1d (10 mol%)
pyrrolidine (10 mol%)
alkene
or
alkyne
R1 C6F13
+
C6F13I
(1.1 equiv)
I
or
R2 R3
I
R2
CH2Cl2, r.t., 16 h
23 W CFL
5
6
N
I
C6F13
Ph
H
I
C6F13
I
C6F13
HO
C6F13
3
7
Ph
2
6b
99%
C6F13
(1.1 eq)
I
+
C8H17
6a
80%
6c
31%
additive, CH2Cl2
r.t., 16 h
23 W CFL
I
C8H17
2
3a
O
I
I
H
C6F13
N
C6F13
O
6
3
6e
Entry
7 (mol%)
Additive (mol%)
Yield (%)
6d
O
51%
78%
C6F13
1
2
3
4
5
6
7
8
9
10
1
-
70
n.r.
99
95
40
95
79
n.r.
n.r.
C6F13
C6F13
I
I
-
I
6g
6f
6h
67%[c]
61%[b]
67%[d]
1
Pyrrolidine (1.3)
Piperidine (1.0)
i-Pr2NH (1.4)
i-Pr2NEt (1.2)
Et3N (1.4)
1d (5.0)
I
C6F13
1
+
C6F13
I
6i
38%[e]
6i'
1
20%[f]
I
I
1
I
C6F13
C6F13
C6F13
C8H17
HO
3
1
6j
6k
6l
22% (E/Z = 88/12)
54% (E/Z = 90/10)[g]
74% (E/Z = 94/6)
100% (E/Z = 90/10)[g]
34% (E/Z = 88/12)
100% (E/Z = 89/11)[g]
1
1
H2O (5.0)
[a] Reaction conditions: 5 (0.75 mmol), C6F13I (1.1 equiv), 1d (0.1 equiv) and
pyrrolidine (0.1 equiv) in CH2Cl2 (7.5 mL), irradiation using 23 W CFL for 16 h
under Ar atmosphere, unless otherwise stated. [b] 56:44 diastereomeric
mixture. [c] 75:25 diastereomer mixture. [d] 3.3 equiv of C6F13I was used. 65:35
diastereomer mixture. [e] 63:37 diastereomer mixture. [f] 64:36 diastereomer
mixture. [g] 1d (1.0 equiv) and pyrrolidine (2.1 equiv) was used.
[a] Reaction conditions: 2 (0.75 mmol), C6F13I (1.1 equiv) in CH2Cl2 (7.5 mL),
irradiation using 23 W CFL for 16 h under Ar atmosphere, unless otherwise
stated.
Scheme 3 depicts a plausible reaction mechanism for this
reaction. Initially, an enamine generated from the amine and
aldehyde forms an EDA complex[11] with the perfluoroalkyl iodide.
EDA complexation was confirmed by optical absorption spectra
(Figure S1).[10] The absorption band extends into longer
wavelengths on the spectrum, which can explain why this reaction
is effective across a wide wavelength range (Table 1, entry 11).
Furthermore, optical absorption spectra of amine and aldehyde
combinations used in Table 1 and perfluorohexyl iodide were
measured (Figure S2). The combination of 1d and pyrrolidine
exhibited a particularly high absorption at 470 nm, indicating the
effectiveness of this combination. Visible light-irradiation on the
EDA complex produces a perfluoroalkyl iodide radical anion and
an enamine radical cation. Then, the perfluoroalkyl radical reacts
with the olefin to give the intermediate radical A. Partial iodine
transfer from another perfluoroalkyl iodide will occur to give the
Scheme 2. Scope of Unactivated Alkenes and Alkynes.
The mechanistic assumption that the enamine, produced from
the aldehyde and the amine, catalyzes the reaction was
investigated by employing the isolated enamine as a catalyst
(Table 3). Surprisingly, the use of 10 mol% enamine lowered the
yield to 70% (entry 1). Furthermore, no reaction occurred with 1
mol% enamine (entry 2), although the reaction of 1 mol% amine
and 1 mol% aldehyde gave the product in 96% yield (Table 1,
Entry 10). We then added a catalytic amount of pyrrolidine and
found that the yield increased to 99% (entry 3). That is, in addition
to the enamine, the free amine likewise participates in the catalytic
reaction. Interestingly, the choice of the added amine was not
limited to pyrrolidine; various other amines proved effective
(entries 4–7). When aldehyde 1d or water were used as additives
in excess, no reaction took place (entries 8 and 9).
iodoperfluoroalkylated
product
(Table
S1,
entry
6).
Simultaneously, the iodide ion reacts with the enamine radical
cation to produce the iodine radical, and the enamine is
regenerated. The iodine radical forms a complex with the free
amine (B),[12] and this iodide–amine complex (B) can effectively
deliver the iodine radical[13] to radical intermediate A, producing
the ATRA product. Moreover, the complexation of iodide and
amine can remove iodine which inhibits the photo-induced
reaction.[14] As a result, the reaction can generate the ATRA
product in good yield. This suggests the involvement of
cooperative catalysis by the enamine and amine.
3
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10.1002/ejoc.201901896
European Journal of Organic Chemistry
COMMUNICATION
[1]
[2]
[3]
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Germany, 2013.
IRf
O
H
N
N
Ph
Ph
+
H
H
Ph
Ph
amine
I
N
I
IRf
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Biomol. Chem., 2015, 13, 11153–11183; d) S. Barata-Vallejo, M. V.
Cooke, A. Postigo, ACS Catal., 2018, 8, 7287–7307.
amine
B
Ph
H
Ph
EDA Complex
N
I
Ph
H
Ph
visible
light
a) D. P. Curran, Synthesis 1988, 1988, 489–513; b) T. Pintauer, K.
Matyjaszewski, Chem. Soc. Rev., 2008, 37, 1087–1097.
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Vázquez, N. S. Nudelman, A. Postigo, J. Fluorine Chem., 2012, 135,
137–143.
N
Rf
Rf
Rf
I
Ph
H
R
I
R
Rf
Ph
RfI
A
R
Scheme 3. Possible reaction mechanism.
[6]
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53, 12064–12068; b) R. Beniazza, M. Douarre, D. Lastécouèresa, J.-M.
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In conclusion, we have developed a metal-free visible light-
induced ATRA of perfluoroalkyl iodide and a wide range of
alkenes and alkynes. The reaction of unactivated olefins
proceeded smoothly with 1 mol% aldehyde and amine. The
reaction proceeded via a cooperative effect of the enamine and
amine. A detailed investigation on the substrate scope and
mechanism of this reaction is ongoing in our laboratory. This
highly sustainable reaction can be applied to the synthesis of
perfluoroalkylated compounds and may provide a plethora of
novel compounds for further studies in the field of
pharmaceuticals and materials.
[7]
[8]
[9]
[10] H. Matsui, M. Murase, T. Yajima, Org. Biomol. Chem., 2018, 16, 7120–
7123.
Acknowledgements
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756.
This work was supported by the Grant-in-Aid for Scientific
Research on Innovative Areas, “Advanced Molecular
Transformations by Organocatalysts” (No. 26105717) and
Scientific Research (C) (16K05687) from MEXT, Japan.
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248, 150–157; b) J. A. LaVerne, L. Wojnarovits, J. Phys. Chem., 1994,
98, 12635–12640; c) H. Rosman, R. M. Noyes, J. Am. Chem. Soc., 1958,
80, 2410–2415.
[13] a) A. Goto, T. Suzuki, H. Ohfuji, M. Tanishima, T. Fukuda, Y. Tsujii, H.
Kaji, Macromolecules 2011, 44, 8709–8715; b) A. Goto, A. Ohtsuki, H.
Ohfuji, M. Tanishima, Y. Tsujii, H. Kaji, J. Am. Chem. Soc., 2013, 135,
11131−11139; c) A. Goto, S. Sanada, L. Lei, K. Hori, Macromolecules
2016, 49, 2511−2517.
Keywords: Perfluoroalkylation • EDA complex • Visible light •
Metal free • ATRA
References:
[14] G. Filippini, M. Silvi, P. Melchiorre, Angew. Chem., Int. Ed., 2017, 56,
4447–4451.
4
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10.1002/ejoc.201901896
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
N
H
I
- Mild and clean reaction
- Various perfluoroalkyl groups
- Small catalytic amount
RfI
Rf
+
O
R
R
Ph
Ph
H
Key Topic
Visible light perfluoroalkylation
TOC text
Metal-free visible light-induced ATRA of perfluoroalkyl iodide was performed. The reaction is
effective for various perfluoroalkyl iodide and unactivated alkenes and alkynes and proceeded smoothly
with 1 mol% aldehyde and amine.
5
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