Diethylzinc-Mediated Radical 1,2-Addition of Alkenes and Alkynes

Article abstract of DOI:10.1021/acs.orglett.1c00669

A novel diethylzinc-mediated radical 1,2-addition of perfluoroalkyl iodides to unactivated alkenes and alkynes is presented, which demonstrates a novel way to generate an ethyl difluoroacetate radical. This method is highly efficient and gives full conversions of the substrates, high yields of the products, and negligible byproducts and requires no column chromatography purifications. The mild conditions enable this protocol to exhibit excellent functional group compatibility.

Full text of DOI:10.1021/acs.orglett.1c00669

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Letter
Diethylzinc-Mediated Radical 1,2-Addition of Alkenes and Alkynes
Xin Li, Songtao He, and Qiuling Song*
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ABSTRACT: A novel diethylzinc-mediated radical 1,2-addition of
perfluoroalkyl iodides to unactivated alkenes and alkynes is
presented, which demonstrates a novel way to generate an ethyl
difluoroacetate radical. This method is highly efficient and gives full
conversions of the substrates, high yields of the products, and
negligible byproducts and requires no column chromatography
purifications. The mild conditions enable this protocol to exhibit excellent functional group compatibility.
8
he 1,2-difunctionalization of alkenes and alkynes is an
ideal reaction because two new functional groups are
metal (TM) catalysts. Some reaction conditions are too harsh
T
to maintain good functional group tolerance. Hence there is
still a demand for a practical protocol that employs simple and
inexpensive catalysts, gives excellent yields, and exhibits broad
functional group compatibility.
Zinc is an essential element for plants, animals, and human
beings. Organozinc compounds have become famous for
Negishi coupling, the Reformatsky reaction, the Fukuyama
reaction, and Baran’s reagent (Figure 1B). In most cases, the
reaction conditions are mild, and thus good functional groups
compatibilities are achieved. Zinc salts are also widely used as
versatile catalysts to catalyze a series of reactions. In addition,
equipped in a single reaction. As a consequence, numerous
elegant methods have been developed to install various kinds
1−6
of groups onto the C−C multiple bonds.
Ordinarily, there
are two common strategies for the 1,2-difunctionalization of
alkenes and alkynes. One is the extensively studied three-
component difunctionalization, which employs two different
reagents to install the two target functional groups one by one
or simultaneously (Figure 1A, route a). The other one, which
10
11
12,13
zinc compounds are found in radical chemistry.
For
example, diethylzinc acts as a source that provides alkyl radicals
12c−k
under the influence of oxygen.
Thus we envision that the
integration of difunctionalization reactions and zinc chemistry
will become a promising research field (Figure 1C).
In this work, we demonstrate a unique reaction mode of
diethylzinc and ethyl iododifluoroacetate in the radical 1,2-
addition of C−C multiple bonds. In addition to achieving high
efficiency, excellent functional group compatibility, and good
stereoselectivity, our protocol realized an ideal “clean
reaction”; that is to say, the starting materials were fully
transformed into the target products and negligible byproducts
were generated, and thus no column chromatography
purifications were demanded after the reaction (Figure 1C).
14
After a preliminary screening of works, 50 mol % of Et Zn
2
efficiently induced a radical 1,2-addition of ethyl iododifluor-
oacetate 1a to allylbenzene 2a, affording the desired product
Figure 1. Integration of 1,2-difunctionalization and zinc chemistry.
3
a in excellent yield at −20 °C (eq 1). After the completion of
uses a single reagent to provide both of the two target
functional groups, is more challenging (route b). Among the
successful examples, perfluoroalkyl halides are regarded as
favorable difunctionalization reagents because fluorine atoms
widely exist in pharmaceutical molecules and halides are
readily transformed into many other groups based on the
the reaction, simple extraction, drying, filtration, and
Received: February 25, 2021
Published: April 5, 2021
reliable S 2 reactions and the abundance of cross-coupling
N
7
−9
reactions (route c). However, most catalytic systems heavily
rely on precious and toxic photocatalysts (PCs) or transition-
7
©
2021 American Chemical Society
https://doi.org/10.1021/acs.orglett.1c00669
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1
5
were obtained (3s and 3t). When two equivalent or
nonequivalent C−C double bonds existed in the same
molecule, this chemistry exhibited good chemoselectivity. For
example, employing 1 equiv of iodide gave a monofunction-
alized product, whereas the other C−C double bond was left
intact (3t). The exocyclic terminal double bond is more
reactive than its cyclic counterpart; only the former was
functionalized when 1 equiv of iodide was employed (3u).
Our attention was then turned to alkyne substrates.
Fortunately, this reaction also worked well for alkynes and
once again showed very good generalizability. For phenyl-
acetylene derivatives, a wide range of substituents on the
aromatic rings were well tolerated (Scheme 2, 5a−p). The data
concentration procedures afforded the target product 3a with
perfect purity. Conventional purification via column chroma-
tography gave a comparable isolated yield.
Because of the lack of a proximal group with a π-electron
system (e.g., aryl, carbonyl, and heteroatom) to stabilize the
nascent alkyl radical intermediates, unactivated alkenes are
much more difficult to difunctionalize than activated alkenes
such as styrene derivatives via radical pathways. Accordingly, a
series of unactivated alkenes bearing various kinds of functional
groups was submitted to the standard reaction conditions to
test the generalizability of our method. For aliphatic terminal
alkenes, the reaction proceeded well and gave excellent yields
despite the structures of the carbon backbones (Scheme 1,
,
a b
Scheme 2. Scope of Terminal and Internal Alkynes
Scheme 1. Scope of Terminal and Internal Alkenes ,
a b
a
Reaction conditions: ICF CO Et 1a (0.2 mmol), alkynes 4 (0.2
2
2
mmol), Et Zn (50 mol %), acetonitrile (2.0 mL), −20 °C, 8 h.
2
b
c
Without column chromatography. E/Z ratios were determined from
the relative intensities of F NMR signals. 25 mol % of Me Zn
instead of Et Zn. Isolated yield.
1
9
d
a
2
Reaction conditions: ICF CO Et 1a (0.2 mmol), alkenes 2 (0.2
e
2
2
2
mmol), Et Zn (50 mol %), acetonitrile (2.0 mL), −20 °C, 16 h.
2
b
c
Without column chromatography. 20 mol % of Me Zn instead of
Et Zn. Ethyl iododifluoroacetate 1a (0.4 mmol) and Et Zn (100 mol
) were used. Isolated yield.
2
d
2
2
revealed that the electronic factor had little influence on the
outcome of the reaction. From electron-donating alkoxys,
alkyls, and halogens to electron-withdrawing formyl and
trifluoromethyl, the high efficiency of the reaction and the
good functional group tolerance were well maintained. In
addition, steric factors did not affect the reaction. For example,
more sterically hindered o- and m-substituted phenylacetylenes
(5l−p) gave almost the same yields as their p-substituted
counterparts (5b−k). The stereoselectivity was good; in most
cases only E isomers were observed. Addtionally, hetero-
cyclic arene was compatible with the reaction (5q). Aliphatic
terminal alkynes readily reacted with the iodides, affording the
target products in high yields. However, the E/Z ratios were
not as good as those of the phenylacetylene derivatives (5r−u),
indicating that the conjugated aromatic rings play a crucial role
in the stereoselectivity of the reaction. A saturated heterocyclic
substrate suffered moderate conversion and required column
chromatography purification to obtain a pure product (5v).
Internal carbon−carbon triple bonds had lower reactivities
e
%
3
b−3d). Diene gave the double-functionalized product when 2
equiv of reagents was employed (3e). The chemistry exhibited
good functional group compatibility. A broad spectrum of
functional groups was tolerated without any problems during
the reaction, affording the corresponding products in perfect
yields. For example, bromide, acetate, benzoate, and sulfonate,
which are good leaving groups under nucleophilic conditions,
all survived during the reaction (3f−j). Substrates bearing
protected alcohols and ether groups efficiently afforded the
target products (3k−m). After the reaction, azide and
protected amines were intact, whereas the difunctionalized
products were obtained in high yields (3n and 3o). Carboxylic
acid derivatives such as nitrile, ester, and amide were also
compatible with the reaction (3p−r). For internal cyclic
alkenes, the desired products were also obtained in good yields
and with high levels of stereocontrol; that is, only trans isomers
16
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under the standard reaction conditions, affording tetra-
substituted olefins in moderate yields (5w,x). Again, alkyne
with a conjugated aromatic ring (5x, E only) gave a better
stereoselectivity than its alkyl counterpart (5w, E/Z = 7:1).
Good functional group compatibility was also achieved at this
time, although moderate conversions and E/Z ratios were
obtained for those differentially functionalized alkynes (5y−
af).
To further explore the generalizability of this chemistry, we
explored other fluoro-containing iodides. Gratifyingly, both
primary and secondary perfluoroalkyls were successfully
incorporated into the C−C double bonds. Desired products
were obtained without any difficulties only at the expense of
lower conversions and the requirements of column chromatog-
raphy purification (Scheme 3).
satisfying to excellent yields. The other functional groups on
the parent compounds were all well tolerated throughout the
reactions. It should be noted that for those examples with
moderate yields, the reactions were also clean. Starting
materials were recovered, and a good mass balance was
obtained (7e).
To shed light on the mechanism, a series of studies was
performed. First, under similar conditions, other organo-
metallic reagents such as n-butyllithium and methyl magne-
sium iodide both failed to promote the reaction, although the
latter is well known in radical processes (Scheme 5A). That
Scheme 5. Mechanism Studies
Scheme 3. Scope of Perfluoroalkyl Iodidesa,b
a
IC F 1 (0.2 mmol), allylbenzene 2a (0.2 mmol), Et Zn (50 mol %),
m
n
2
b
acetonitrile (2.0 mL), −20 °C, 16 h. Isolated yield.
More importantly, the reaction showed good potential for
the late-stage structural modifications of natural products and
pharmaceutical molecules (Scheme 4). A series of derivatives
of those compounds, such as camphorsulfonic acid, estrone,
(
+)-fenchol, ibuprofen, dihydrocholesterol, and (+)-dehydroa-
bietylamine, all reacted well to give the desired products in
result also excluded a base-catalyzed mechanism, which is one
8a
Scheme 4. Late-Stage Functionalization of Natural Product
and Pharmaceutical Molecule Derivatives
probable mechanism in Hu’s work. To determine whether
metal zinc is the real catalytic species, we examined zinc
powder, as well as other reductive metals (Cu, Mn, Mg, Fe), to
promote the reaction. However, even at elevated temperatures,
those metals all failed to give the desired products (Scheme
,
a b
5
A). Hence the data excluded a metal-promoted mechanism,
17
which is proposed by several groups. The reaction performed
well in the dark, thus excluding a light-induced mechanism
(
Scheme 5B). The addition of TEMPO totally shut down the
reaction, whether or not alkene 2a was added, and the
TEMPO-captured ethyl difluoroacetate radical 8 was detected
by gas chromatography−mass spectrometry (GC-MS), which
strongly indicated that radical species were involved in the
reaction (Scheme 5C). Moreover, a couple of radical ring-
opening and ring-closure reactions further consolidated a
radical mechanism. For example, α-pinene gave a ring-opening
product 9 (Scheme 5D), whereas allyl ether and allyl amine
substrates both gave ring-closure products 10 (Scheme 5E). In
combination with the result that no protonated products were
isolated after the reaction, these data also excluded a
18
carbozincation mechanism. Further studies showed that
after reacting with 1.0 equiv of diethylzinc in the absence of
alkenes or alkynes, ICF CO Et fully transformed into enolate I
a
ICF CO Et 1a (0.2 mmol), alkenes 2 (0.2 mmol), Et Zn (50 mol
2
2
2
b
%
), acetonitrile (2.0 mL), −20 °C, 16 h. Without column
2
2
c
d
because its protonated product HCF CO Et 11 was detected
chromatography. Isolated yield. ICF CO Et 1a (0.2 mmol), alkenes
2
2
2
2
1
9
2
(0.1 mmol), Et Zn (100 mol %), acetonitrile (2.0 mL), rt, 16 h.
as the only fluorine-containing species by crude F NMR
(Scheme 5F). Trace amounts of oxygen were proven to be
2
e
19
Yield of recovered starting material.
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Letter
necessary to initiate the reaction, as only <5% product was
obtained when the reaction was performed in freshly distilled
MeCN with freeze−pump−thaw cycling.
palladium-catalyzed Sonogashira coupling and a cobalt-
catalyzed Kumada coupling. Both the vinyl iodide and the
alkyl iodide successfully reacted with the corresponding
coupling partners to afford the desired products 14 and 15
in good yields (Scheme 7C,D).
In conclusion, we have developed a simple but efficient
protocol to install two functional groups of synthetic values
onto C−C multiple bonds. This work demonstrates a novel
way to generate an ethyl difluoroacetate radical. The mild
conditions, high yields, excellent functional group compati-
bility, and good stereoselectivity make our protocol of great
synthetic importance and a good complement to the existing
catalytic systems. The application of zinc-mediated radical
chemistry to other reactions is under investigation in our lab.
On the basis of those results, a probable mechanism is
proposed. First, diethylzinc undergoes metal/iodine exchange
upon reaction with ethyl iododifluoroacetate 1a to afford
20
intermediate I (Scheme 6, step 1). In the meantime,
Scheme 6. Proposed Mechanism
ASSOCIATED CONTENT
sı Supporting Information
■
*
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00669.
Detailed experimental procedures, characterization data,
1
13
diethylzinc reacts with a trace amount of oxygen to release
ethyl radical II (step 2). The latter then attacks I to produce
ethyl difluoroacetate radical III and regenerate the diethylzinc
and copies of H and C NMR spectra (PDF)
12
AUTHOR INFORMATION
Corresponding Author
■
(
step 3). Radical III then undergoes an atom transfer radical
2b
addition (ATRA) reaction; that is, radical III first adds to a
C−C multiple bond to form an adduct radical IV (step 4),
which captures an iodide radical from the starting material 1a
to furnish the target addition product (step 5). Meanwhile, this
process regenerates the difluoroacetate radical III, which could
react with another molecule of substrates.
Qiuling Song − Institute of Next Generation Matter
Transformation, College of Materials Science & Engineering,
Huaqiao University, Xiamen 361021, Fujian, China; State
Key Laboratory of Organometallic Chemistry and Key
Laboratory of Organofluorine Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China; orcid.org/0000-0002-9836-
The synthesized products are versatile building blocks and
exhibit broad synthetic utility. Both the iodide and the
difluoroester are readily transformed into other groups. For
example, iodide in compound 3b was smoothly substituted by
8
860; Email: qsong@hqu.edu.cn
Authors
sodium azide via a S 2 reaction (Scheme 7A). The
N
Xin Li − Institute of Next Generation Matter Transformation,
College of Materials Science & Engineering, Huaqiao
University, Xiamen 361021, Fujian, China
Scheme 7. Synthetic Utilities of the Addition Products
Songtao He − Institute of Next Generation Matter
Transformation, College of Materials Science & Engineering,
Huaqiao University, Xiamen 361021, Fujian, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00669
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge the financial support from the National
Natural Science Foundation of China (21772046 and
■
2193103). We also thank the Instrumental Analysis Center
of Huaqiao University.
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