Silver-Mediated Decarboxylative Fluorodiiodination of Alkynoic Acids: Synthesis of Regio- and Stereoselective Fluoroalkenes

Article abstract of DOI:10.1021/acs.orglett.9b00597

A variety of arylalkynoic acids reacted with 1,3-diiodo-5,5-dimethylhydantoin and HF·pyridine in the presence of AgOAc to provide the corresponding 1-fluoro-2,2-diiodovinylarenes in good yields and high regioselectivity. In addition, Pd-catalyzed cross-co

Full text of DOI:10.1021/acs.orglett.9b00597

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Silver-Mediated Decarboxylative Fluorodiiodination of Alkynoic
Acids: Synthesis of Regio- and Stereoselective Fluoroalkenes
Aravindan Jayaraman and Sunwoo Lee*
Department of Chemistry, Chonnam National University, Gwangju 61186, Republic of Korea
S
* Supporting Information
ABSTRACT: A variety of arylalkynoic acids reacted with 1,3-
diiodo-5,5-dimethylhydantoin and HF·pyridine in the presence
of AgOAc to provide the corresponding 1-fluoro-2,2-diiodovi-
nylarenes in good yields and high regioselectivity. In addition,
Pd-catalyzed cross-coupling reaction of 1-fluoro-2,2-diiodovi-
nylarenes afforded diaryl coupling products in the Suzuki
reaction and monoaryl coupling products with high stereo-
selectivity in the Hiyama reaction. It was found that C−F-
activated borylation of fluoroalkenes using Pd catalyst afforded
the vinylboranes with good yields.
Scheme 1. Synthesis of Fluoroalkenes
any biological and medicinal products, as well as
Mimportant functional materials, contain the fluorine
functionality.1 Substitution of hydrogen with fluorine in
organic materials can dramatically change the reactivity and
the chemical, physical, and biological properties of the
corresponding compounds.2 As a consequence, fluorinated
compounds have recently gained considerable attention in
various fields, and the number of methodologies introducing
the fluorine functionality into organic compounds has
increased drastically over the last few decades.3
Fluoroalkene, one of the numerous fluorine-containing
compounds, is an important structural motif found in many
bioactive compounds and is a useful building block.4 A variety
of synthetic methods for fluoroalkenes have been reported in
the literature, and hydrofluorination of alkynes is one such
straightforward method (Scheme 1a).5 Sadighi first reported
hydrofluorination of alkynes using Au catalyst to furnish
fluoroalkenes in good yields. A number of Au-catalyzed
hydrofluorination reactions of alkynes have been developed
by several groups. In addition, it was reported that alkynes
having a carbonyl group could be converted into the
corresponding fluoroalkenes under metal-free or copper
catalysis conditions (Scheme 1b).6
Moreover, fluoroalkene derivatives 1,2-bromofluoro- and
1,2-fluoroiodoalkenes have received considerable attention as
useful fluorinated building blocks because these vinyl bromides
and iodides can be further transformed into versatile molecules
via cross-coupling reactions (Scheme 1c). Jiang demonstrated
that 1,2-bromofluoroalkenes could be synthesized by the
reaction of terminal alkynes with NBS/AgF.7 Synthesis of 1,2-
fluoroiodoalkenes was accomplished by the fluoroiodination of
alkynes employing HF-based reagents along with the iodine
reagents such as I2, Tol-IF2, IF5, PhIO, and 1,3-diiodo-5,5-
dimethylhydantoin (DIH).8 In contrast, much less attention
has been paid toward gem-dihalo-substituted fluoroalkenes,
although in theory, they are highly likely to be employed as
coupling partners in the cross-coupling reactions for the
preparation of mono- and disubstituted fluoroalkenes. It has
been reported that the preparation of gem-dibromo- and gem-
dichlorofluoroalkenes from aldehydes requires a multistep
process (Scheme 1d).9 Therefore, simple and one-step
synthetic methods are required.
Received: February 17, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00597
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Given our interest in the decarboxylation of alkynoic
carboxylic acids for the synthesis of halogenated compounds,
we recently reported the first general synthesis of 2,2,2-
trichloroacetophenone, 2,2,2-tribromoacetone, and 1,2,2-tri-
bromoalkene via decarboxylative halogenation of alkynoic
acids.10 We found that water works as a nucleophile and adds
to the alkyne in the presence of the halogen source. From these
studies, we envisioned that 1-fluoro-2,2-diiodovinyl arenes
could be obtained via the decarboxylation of alkynoic acid if a
fluorine reagent worked as a nucleophile in the presence of the
iodine source.
Moreover, we paid attention to developing the selective
mono- and diaryl coupling reactions with 1-fluoro-2,2-
diiodovinylarenes because they can further be readily trans-
formed into a variety of molecules bearing a fluoroalkene
group. Although many synthetic methods for fluoroalkenes
have been developed,11 preparation of (Z)-fluoroalkenes is
much less explored.12 Herein, we report the synthesis of 1-
fluoro-2,2-diiodovinyl arenes from alkynoic acids and demon-
strate their applications in the selective aryl cross-coupling
reactions.
Table 1. Optimal Conditions for the Synthesis of 1-Fluoro-
2,2-diiodovinylbenzene
a
b
yield (%)
F source
(equiv)
temp
(°C)
additive
(20 mol %)
entry
solvent
2a
3a
1
2
3
4
5
Py·HF (5) CH3CN
25
25
25
25
25
18
0
0
0
51
8
20
24
2
KF (5)
CH3CN
CH3CN
CH3CN
CH3CN
CsF (5)
Et3N·3HF
Py·HF
6
(15)
6
Py·HF
CH2Cl2
THF
25
25
25
25
40
40
40
40
40
80
17
3
26
55
22
2
(15)
7
Py·HF
(15)
Py·HF
(15)
Py·HF
(15)
Py·HF
(15)
Py·HF
(15)
Py·HF
(15)
Py.HF
(15)
Py.HF
(20)
Py.HF
(15)
8
toluene
acetone
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
2
To find optimal conditions, phenyl propiolic acid was
chosen as a standard substrate and reacted with 1,3-diiodo-5,5-
dimethylhydantoin (DIH) and different fluorine reagents. The
results are summarized in Table 1
9
8
10
11
12
13
14
15
62
41
69
3
AgI
14
8
It was found that 1-fluoro-2,2-diiodovinylbenzene 2a was
formed in 18% yield when Py·HF was treated with 1a and DIH
at room temperature (entry 1). When either KF, CsF, or Et3N·
3HF was employed as a fluoride source, triiodoalkene 3a was
formed without the formation of 2a (entries 2−4). When the
amount of Py·HF was increased to 15 equiv, the yield of 2a
increased to 51%; however, byproduct 3a was still formed
(entry 5). The reactions in other solvents such as CH2Cl2,
THF, toluene, and acetone did not give satisfactory results
(entries 6−9). Increasing the reaction temperature to 40 °C
afforded 62% yield of 2a with a small amount of 3a. In
addition, iodoethynylbenzene was formed with 12% yield
(entry 10). Addition of AgI to the reaction mixture did not
enhance the yield of 2a; however, the reaction with Ag2O
provided a 69% yield of 2a (entry 12). Finally, when the
reaction was conducted with a catalytic amount of AgOAc (20
mol %), 2a was formed selectively in 82% yield without the
formation of 3a. Moreover, no iodoethynylbenzene was found
(entry 13). Product 2a was successfully isolated in 81% yield.
Increasing the amount of Py·HF did not improve the yield of
2a (entry 14). The reaction at 80 °C did not give a satisfactory
result (entry 15). The identification of structure 2a was
confirmed by 2D HSQC (see the Supporting Information).13
Under these optimal conditions, we evaluated this trans-
formation with a number of arylalkynoic acids (Scheme 2).
Methyl-substituted arylpropiolic acids afforded the corre-
sponding products 2b, 2c, 2d, and 2e in good yields. 4-Ethyl-
and 4-tert-butyl-substituted phenyl propiolic acid gave 2f and
2g in 82% and 84% yields, respectively. Arylpropiolic acids
having 2-methoxy-, 4-methoxy-, and 3,4-dioxane groups
produced the corresponding 1-fluoro-2,2-diiodovinylarenes
2h, 2i, and 2j, respectively, in good yields. 1,1′-Biphenyl-4-
yl-, 1-naphthyl-, and 2-naphthylpropiolic acids were trans-
formed into 2k, 2l, and 2m in 72%, 71%, and 76% yields,
respectively. Bromo-, chloro-, and fluoro-substituted phenyl-
propiolic acids provided the desired products 2n, 2o, 2p, 2q,
and 2r in yields ranging between 56 and 64%. Alcohol, nitrile,
ketone, ester, and aldehyde groups exhibited good tolerance in
Ag2O
c
AgOAc
AgOAc
AgOAc
82 (81)
82
0
0
73
5
a
Reaction conditions: 1a (1.0 mmol), DIH (1.1 mmol), and F source
b
were reacted in solvent (4.0 mL) for 16 h. Determined by 1H NMR
and gas chromatography with an internal standard. Isolated yield.
c
the formation of 2s, 2t, 2u, 2v, and 2w, respectively.
Arylpropiolic acid bearing a nitro group furnished 2x and 2y
in a slightly lower yield. Although the alkyl-substituted
propiolic acids such as octynoic acid afforded desired product
2z, we failed to isolate it in pure form as it could not be
separated from the byproduct (1,1,2-triiodoheptene) by
column chromatography. From these results, it could be
generalized that (i) the steric hindrance of substituents on the
aryl ring of alkynoic acids did not affect this transformation,
and the arylalkynoic acids bearing substituents at the ortho,
meta, and para positions worked well, and (ii) the electronic
properties of different substituents on the aryl ring influenced
the yields of the products, with the electron-donating groups
increasing the efficiency of the reaction, and resulting in
product in excellent yield, and the electron-withdrawing groups
decreasing the efficiency of the reaction to a certain extent.
The broad tolerance toward the functional groups such as
halogen, alcohol, nitrile, ketone, ester, aldehyde, and nitro
offered a great opportunity to further functionalize the
corresponding products.
Afterward, to study the reaction pathway, control experi-
ments were carried out (Scheme 3). When phenylpropiolic
acid was reacted with DIH in the absence of Py·HF,
iodoethynylbenzene (A) was formed in 91% yield. We found
that (1-fluoro-2,2-diiodovinyl)benzene (2a) was formed in
B
DOI: 10.1021/acs.orglett.9b00597
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Synthesis of 1-Fluoro-2,2-diiodovinylarenes
Table 2. Pd-Catalyzed Mono- and Diaryl Coupling
Reactions of 2a
b
yield (%)
a
entry
Ar-M
1a/Ar-M (equiv)
conditions
6a
7a
1
2
3
4
5
6
7
4a
5a
4a
4a
5a
5a
5a
1.0/2.5
1.0/2.5
1.0/1.1
1.0/2.5
1.0/1.1
1.0/2.5
1.0/5.0
A
B
A
B
B
A
B
91
0
34
40
0
0
73
9
0
5
0
0
0
72
a
Conditions: (A) 5 mol % of Pd2(dba)3, 20 mol % of PPh3, and
K2CO3 (3.0 equiv) were employed in toluene/H2O/EtOH at 80 °C
for 12 h; (B) 10 mol % of Pd(OAc)2, 20 mol % of DABCO, and
TBAF (3.0 equiv) were employed in dioxane at 80 °C for 12 h.
b
Isolated yield.
product was found and only deiodo monoaryl coupling
product 7a was formed in 73% yield (entry 2). It was found
that only (Z)-7a was formed in the reaction mixture. The
Suzuki coupling of 2a and 4a afforded 6a as the major product
even when 1.1 equiv of 4a was employed, and the reaction was
conducted under conditions B (entries 3 and 4). When 2a was
allowed to react with 1.1 equiv of 5a, only 7a was formed in 5%
yield (entry 5). In addition, neither 6a nor 7a was formed
when the Hiyama coupling was carried out under conditions A
(entry 6). When 5.0 equiv of 5a was used, only 7a was formed
with 72% yield (entry 7).
a
Reaction conditions: 1 (2.0 mmol), DIH (2.2 mmol), Py.HF (30.0
mmol), and AgOAc (0.4 mmol) were reacted in CH3CN at 40 °C for
16 h. Isolated yields in parentheses. Compound 2z was obtained with
1,1,2-triiodohept-1-ene.
We evaluated the Suzuki coupling reactions of 1-fluoro-2,2-
diiodovinylarenes and arylboronic acids under conditions A. As
shown in Scheme 4, 2a reacted with substituted arylboronic
acids to furnish diaryl coupling product 6 in good yields. In
addition, 1-fluoro-2,2-diiodovinylarenes, having substituents
Scheme 3. Control Experiments
Scheme 4. Suzuki Coupling Reactions of 1-Fluoro-2,2-
a
diiodovinylarenes
88% yield when iodoethynylbenzene was treated under the
standard conditions. From these results, it was elucidated that
alkynyl iodide was an intermediate in this transformation. We
suggest that alkynyl iodide reacts with DIH to provide a
iodonium bridged ion which is opened by the fluoride ion.
We further studied the application of 1-fluoro-2,2-
diiodovinylarenes as coupling partners in the Pd-catalyzed
cross-coupling reactions. We found that the 2,2-diiodovinyl
group showed different reactivities in the Suzuki and Hiyama
cross-coupling reactions. The results are summarized in Table
2 (see the Supporting Information for details).
When 2.5 equiv of p-tolylboronic acid was treated with 2a
under conditions A, diaryl coupling product 6a was formed in
91% yield (entry 1). However, when trimethoxy-p-tolylsilane
was allowed to react under conditions B, no diaryl coupled
a
Reaction conditions: 1 (1.5 mmol), 4 (3.75 mmol), Pd2(dba)3
(0.075 mmol), PPh3 (0.3 mmol), and K2CO3 (4.5 mmol) were
reacted in toluene/H2O/EtOH at 80 °C for 12 h.
C
DOI: 10.1021/acs.orglett.9b00597
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
such as methyl and chloride, also afforded diaryl coupling
products 6g, 6h, and 6i in good yields.
resulted in good yields of the cross-coupling products in both
Suzuki and Hiyama coupling reactions. We also demonstrated
that C−F bond activation of fluoroalkenes for the synthesis of
vinylboranes.
The Hiyama coupling reactions were also tested with 1-
fluoro-2,2-diiodovinylarenes and aryl siloxanes under con-
ditions B. As expected, all of the tested arylsiloxanes exclusively
afforded the monoaryl coupling products in good yields. It was
noteworthy that only (Z)-fluoroethene derivatives were
observed in the formation of monoaryl coupling product 7
(Scheme 5). The reaction mechanism of the coupling reactions
with 1-fluoro-2,2-diiodovinylarenes is not clear at this time.14
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00597.
Experimental procedures and spectral data for the
products (PDF)
Scheme 5. Hiyama Coupling Reactions of 1-Fluoro-2,2-
diiodovinylarenes
a
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sunwoo@chonnam.ac.kr.
ORCID
Sunwoo Lee: 0000-0001-5079-3860
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Research
Foundation of Korea (NRF) grant funded by the Korea
government (MSIP) (NRF-2012M3A7B4049655, NRF-
2015R1A4A1041036, NRF-2017R1A2B2002929). The spec-
tral and HRMS data were obtained from the Korea Basic
Science Institute, Gwangju Center, and Daegu Center.
a
Reaction conditions: 1 (1.5 mmol), 5 (3.75 mmol), Pd(OAc)2 (0.15
mmol), DABCO (0.3 mmol), and TBAF (4.5 mmol) were reacted in
1,4-dioxane at 80 °C for 12 h.
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