Blue Light Induced Difluoroalkylation of Alkynes and Alkenes

Article abstract of DOI:10.1021/acs.orglett.9b03855

The difluoroalkylation of alkynes and alkenes by direct photoexcitation of ethyl difluoroiodoacetate is described. Under catalyst- and oxidant-free conditions, iododifluoroalkylation and hydrodifluoroalkylation products were generated from alkynes, and difluoroalkylation products were prepared from alkenes. This methodology provides a streamlined access to difluoroalkylated organic compounds starting from simple alkynes or alkenes.

Full text of DOI:10.1021/acs.orglett.9b03855

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Blue Light Induced Difluoroalkylation of Alkynes and Alkenes
Kangkui Li,‡,§ Xuexin Zhang,‡,§ Jingchao Chen,*,‡ Yang Gao,‡ Chunhui Yang,‡ Keyang Zhang,‡
Yongyun Zhou,†,‡ and Baomin Fan*,†,‡
†School of Chemistry and Environment, Yunnan Minzu University, Yuehua Street, Kunming, 650500, China
‡Institution Key Laboratory of Chemistry in Ethnic Medicinal Resources (Yunnan Minzu University), State Ethnic Affairs
Commission & Ministry of Education, Kunming, 650500, China
S
* Supporting Information
ABSTRACT: The difluoroalkylation of alkynes and alkenes
by direct photoexcitation of ethyl difluoroiodoacetate is
described. Under catalyst- and oxidant-free conditions,
iododifluoroalkylation and hydrodifluoroalkylation products
were generated from alkynes, and difluoroalkylation products
were prepared from alkenes. This methodology provides a
streamlined access to difluoroalkylated organic compounds
starting from simple alkynes or alkenes.
he introduction of fluorine atoms into organic molecules
genation of hydrazobenzenes10 and transfer hydrogenation of
Tmay lead to dramatic changes in their properties such as cyclic N-sulfonylimines.11 We then questioned whether the
lipophilicity, metabolic stability, and bioavailability.1 Fluorine-
direct photoexcitation of specific functional groups by taking
advantage of the visible light absorptivity to provide an efficient
method for the synthesis of useful synthons. Herein, we
describe three photocatalyst- and oxidant free-difluoroalkyla-
tion reactions with ethyl difluoroiodoacetate: (i) iododifluor-
oalkylation of alkynes; (ii) hydrodifluoroalkylation of alkynes;
(iii) the difluoroalkylation of alkenes.
containing structural motifs play important roles in pharma-
ceuticals and agrochemicals; more than 20% of the
pharmaceuticals and agrochemicals on the market are organo-
fluorines. Thus, the selective introduction of fluorine or
fluorinated groups into the drug candidates has been regarded
as a powerful strategy in drug design and screening.2 Direct
fluoroalkylation has received much attention, as it serves as a
straightforward method for the synthesis of organofluorines.
Over the past decade, remarkable progress has been made in
the transition-metal catalyzed fluoroalkylation of arenes.3
Although the traditional fluoroalkylation reactions by using
transition metal catalysts are powerful,4 the addition reaction
of halo-fluoroalkanes to alkenes or alkynes via the atom
transfer radical addition (ATRA) strategy has emerged as an
attractive methodology, which was facilitated by transition
metal,5 light,6 or radical initiators.7 The advantages of this
method include the easy availability of the reagents and the
great synthetic versatility of the halofluoroalkene products (for
cross-coupling5b,c,7a or functional group transformations8).
However, the use of transition metal, photocatalysts, or radical
initiators may undermine its industrial applications due to
some drawbacks, as it is expensive and oxygen sensitive and
may leave toxic trace metal contaminants. Because of the broad
applications of halofluoroalkenes, the development of eco-
friendly, synthetically efficient methodologies from easily
accessible raw materials under simple and mild reaction
conditions is still highly desirable.
We initially began our studies by evaluating the effect of a
suitable base, which was reported to promote the generation of
free radicals.12 Reaction optimization was conducted with 1-
phenyl-1-propyne 1a and ethyl difluoroiodoacetate (2 equiv)
under irradiation with a blue light-emitted diode (LED) at
room temperature in the presence of a base (Table 1). To our
delight, the generation of the desired iododifluoroalkylation
product 2a was observed by using some organic bases such as
TEA, TMEDA, DIPEA, and DBU (Table 1, entries 1−4). The
inorganic bases were also effective, and the use of Cs2CO3 has
given a good yield of 88% (Table 1, entries 5−8). Next, some
other solvents besides acetonitrile were screened. DMF and
DMSO proved to be effective (Table 1, entries 9−10).
Interestingly, no iododifluoroalkylation product 2a was
detected by using THF as a reaction solvent, but gave the
hydrodifluoroalkylation product 3a in 68% yield (Table 1,
entry 11). It could be explained by the transfer hydrogenation
of the vinyl radical intermediate with THF as a hydrogen
donor.12 However, no 3a was detected by using 1,4-dioxane
instead of THF (Table 1, entry 12). By reacting at a high
concentration, 2a and 3a were obtained with 89% and 81%
yield, respectively (Table 1, entries 13−14). The following
control experiments established the requirement of light. No
In this decade, a surge of interest has led the photocatalyzed
reactions to the forefront of synthetic methodology, and the
processes serve as environmentally friendly methods for
promoting selective radical reactions.9 Our group has
previously investigated the photocatalyzed oxidative dehydro-
Received: October 29, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03855
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Reaction Conditions Optimization
Scheme 1. Substrate Scope of Iododifluoroalkylation
b
Yield (%)
2a
63
72
40
32
25
50
88
7
73
82
trace
69
89
trace
nd
11
nd
Entry
Base
TEA
TMEDA
DIPEA
DBU
Solvent
Time (h)
3a
1
2
3
4
5
6
7
8
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
DMSO
THF
1,4-dioxane
CH3CN
THF
24
24
24
24
24
24
12
24
16
16
60
60
10
60
12
24
24
trace
trace
nd
nd
nd
nd
nd
nd
nd
nd
68
nd
nd
81
nd
nd
nd
Na2CO3
K2CO3
Cs2CO3
KOtBu
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
10
11
12
c
13
c
14
c d
,
15
16
17
CH3CN
CH3CN
CH3CN
c e
,
f
a
Reaction conditions: 1a (0.2 mmol), ICF2COOEt (0.4 mmol), and
base (0.4 mmol) in solvent (2 mL) were irradiated by 30 W blue LED
a
Reaction conditions: 1 (0.2 mmol), ICF2COOEt (0.4 mmol), and
Cs2CO3 (0.4 mmol) in CH3CN (1 mL) was irradiated by 30 W blue
LED at room temperature. Notes: Yields were calculated by the total
isolated yields of E- and Z-products; the E/Z ratios were determined
b
at room temperature. The total isolated yield of E- and Z-products
c
(unreacted 1a was responsible for the cases with low yield). 1 mL of
d
e
f
solvent was used. Reacted in dark. Reacted in natural light. The
BrCF2COOEt (0.4 mmol) was used instead of ICF2COOEt. Nd - not
determined.
by 19F NMR and H NMR spectroscopy.
1
a
Scheme 2. Substrate Scope of Hydrodifluoroalkylation
reaction proceeded in the dark (Table 1, entry 15), and the
reaction exposed to natural light reacted slowly to give 2a in
11% yield over 24 h (Table 1, entry 16). By using the
difluorobromoacetate instead of difluoroiodoacetate, no
reaction took place (Table 1, entry 17).
With the optimized conditions in hand, we then investigated
the scope of the iododifluoroalkylation reaction with various
alkynes (Scheme 1). In general, a wide range of alkynes could
be transformed into the corresponding iododifluoroalkylation
products, and the (E) stereoisomers were obtained as the
major isomers. With electron-withdrawing or electron-
donating groups on the para-positions, the internal alkynes
reacted smoothly to give the fluorine tagged benzyl iodides
(2b−e). 1-Phenyl-1-butyne and the internal alkyne with alkyl
substituents also reacted well (2f−g). Slightly reduced yields
were obtained by using alkynes with electron-withdrawing
substituents (2h−i). Next, a range of terminal alkynes was
investigated. In general, terminal alkynes bearing aryl groups of
different electronic properties with substituents at various
positions were all suitable for the present transformation, and
preferable E/Z stereoselectivities were obtained by the increase
of steric hindrance (2j−t). Terminal alkynes with pyridyl or
alkyl substitutions also participated readily in the present
protocol (2u−v).
a
Reaction conditions: 1 (0.2 mmol), ICF2COOEt (0.4 mmol), and
Cs2CO3 (0.4 mmol) in THF (1 mL) was irradiated by 30 W blue
LED at room temperature. Notes: Yields were calculated by the total
isolated yields of E- and Z-products; the E/Z ratios were determined
by 19F NMR and H NMR spectroscopy.
1
only the iododifluoroalkylation product 2j (76% yield) was
obtained.
Furthermore, the current reaction condition was successfully
applied to the alkenes. Interestingly, the reactions have
afforded the difluoroalkylation products rather than the
iododifluoroalkylation products (Scheme 3). A broad range
of alkenes with various functional groups, such as alkyls, alkoxy,
and halogens, in different positions reacted well with excellent
E/Z stereoselectivity, with no obvious steric effect observed
(5a−j). A 1,1-disubstituted alkene also gave the desired
Subsequently, by using THF as reaction solvent, some
representative alkyl-substituted alkynes were subjected to the
optimized reaction conditions (Scheme 2). All of the tested
alkynes were successfully transformed to the hydrodifluor-
oalkylation products as diastereoisomers in about 1:1 E/Z
ratios in good yields. However, by using ethynylbenzene 1j,
B
DOI: 10.1021/acs.orglett.9b03855
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Organic Letters
Letter
a
Finally, to rationalize the reaction pathway, several control
experiments were performed (Scheme 5). The reaction was
Scheme 3. Substrate Scope of Difluoroalkylation
Scheme 5. Control Experiments
a
Reaction conditions: 4 (0.2 mmol), ICF2COOEt (0.4 mmol), and
Cs2CO3 (0.4 mmol) in CH3CN (1 mL) was irradiated by 30 W blue
LED at room temperature. Notes: Yields were calculated by the total
isolated yields of E- and Z-products; the E/Z ratios were determined
completely quenched in the presence of 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO), and the trapped product 6 was
obtained as expected (Scheme 5a). This result indicated that a
difluoroalkyl radical might be involved in this process. By
irradiation of 2a with THF as solvent, the corresponding
hydrodifluoroalkylation product 3a was obtained in 77% yield
(Scheme 5b), but the reaction did not take place in the dark
(Scheme 5c). These results indicated the iododifluoroalkyla-
tion product 2a could serve as the intermediate in the
hydrodifluoroalkylation reaction, which was promoted by the
LED irradiation. The deuterium-difluoroalkylation reaction by
using THF-d8 as solvent has successfully afforded product 3a-
D with 80% deuterium incorporation (Scheme 5d). Therefore,
the THF played a role as the hydrogen donor in the
hydrodifluoroalkylation reactions. Ultraviolet−visible spectros-
copy of ICF2COOEt showed a strong absorption signal at 360
nm, while none was observed for 1a. This showed that it is
ICF2COOEt that absorbs light in the present reaction (please
see Supporting Information for details).
On the basis of the results of control experiments and
related references,5−7,13 the proposed mechanism of the
difluoroalkylation reactions is outlined in Scheme 6. The
reactions are initiated with the difluoroalkyl radical A, which is
generated directly by photoexcitation of ethyl difluoroiodoa-
cetate. In the case of an alkyne, radical A adds to the prop-1-
yn-1-ylbenzene forming a vinyl radical B. The latter could
abstract an iodine atom to result in formation of the
by 19F NMR and H NMR spectroscopy.
1
product in good yield (5k). Benzofuran and coumarin were
selectively difluoroalkylated at specific positions, respectively
(5l−m). When the 3,4-dihydro-2H-pyran, which is an aliphatic
internal alkene bearing a nonconjugated double bond, was
employed, the target difluoroalkylation product was obtained
in reduced yield (5n). By using a long-chain aliphatic alkene,
the iododifluoroalkylation product 5o′ was obtained as the
major product (74% yield). It is interesting to note that the
iododifluoroalkylation product 5o′ could transfer to the
difluoroalkylation product 5o in the reaction mixture, finally
giving 5o in 73% yield over 28 h.
Importantly, three gram-scale experiments have been
demonstrated, and all of the reactions proceeded smoothly
with satisfactory results (Scheme 4). Thus, the present
synthetic methodology may offer a cost-effective practical
access to highly functionalized difluoroalkylated molecules.
Scheme 4. Gram-Scale Experiments
Scheme 6. Proposed Reaction Mechanism
a
Yield was calculated from NMR spectrum.
C
DOI: 10.1021/acs.orglett.9b03855
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b03855.
Experimental procedures and characterization data
(PDF)
(6) (a) Wallentin, C.-J.; Nguyen, J. D.; Finkbeiner, P.; Stephenson,
C. R. J. J. Am. Chem. Soc. 2012, 134, 8875−8884. (b) Zhong, J.-J.;
Yang, C.; Chang, X.-Y.; Zou, C.; Lu, W.; Che, C.-M. Chem. Commun.
2017, 53, 8948−8951. (c) Mizuta, S.; Verhoog, S.; Engle, K. M.;
Khotavivattana, T.; O’Duill, M.; Wheelhouse, K.; Rassias, G.;
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: chenjingchao84@163.com (C.J.-C.).
*E-mail: adams.bmf@hotmail.com (F.B.-M.).
ORCID
́
Medebielle, M.; Gouverneur, V. J. Am. Chem. Soc. 2013, 135,
2505−2508. (d) Iqbal, N.; Jung, J.; Park, S.; Cho, E. Angew. Chem.,
Int. Ed. 2014, 53, 539−542. (e) Rawner, T.; Lutsker, E.; Kaiser, C. A.;
Reiser, O. ACS Catal. 2018, 8, 3950−3956. (f) Yu, C.; Iqbal, N.; Park,
S.; Cho, E. Chem. Commun. 2014, 50, 12884−12887. (g) Yajima, T.;
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Adv. Synth. Catal. 2019, 361, 3723−3728. (i) Liu, Y.; Chen, X.-L.;
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Baomin Fan: 0000-0003-1789-3741
Author Contributions
§K.-K.L. and X.-X.Z. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We are grateful to the National Natural Science Foundation of
China (21961045, 21572198), the Applied Basic Research
Project of Yunnan Province (2017FA004, 2018FB021), the
Department of Education of Yunnan Province (2019Y0198),
and Yunnan Provincial Key Laboratory Construction Plan
Funding of Universities for their financial support.
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