Intermolecular Iodofluoroalkylation of Unactivated Alkynes and Alkenes Mediated by Manganese Catalysts

Article abstract of DOI:10.1002/adsc.201901556

An approach for iodofluoroalkylation of unactivated alkynes and alkenes facilitated by an earth-abundant and inexpensive manganese catalyst, Mn₂(CO)₁₀, is reported. This protocol employs visible light as the energy input and shows a wide substrate scope and high functional-group compatibility. A variety of synthetically useful fluoroalkylated alkyl and alkenyl iodides can be prepared in moderate to excellent yields. The reaction features high efficiency, operational simplicity, scalability, as well as excellent chemo-, regio-, and E/Z selectivities. (Figure presented.).

Full text of DOI:10.1002/adsc.201901556

Title: Intermolecular Iodofluoroalkylation of Unactivated Alkynes and
Alkenes Mediated by Manganese Catalysts
Authors: Yun-Xing Ji, Lu-Jun Wang, Weisi Guo, Qirui Bi, and Bo Zhang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901556
Link to VoR: http://dx.doi.org/10.1002/adsc.201901556

10.1002/adsc.201901556
Advanced Synthesis & Catalysis
Very Important Publication
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Intermolecular Iodofluoroalkylation of Unactivated Alkynes
and Alkenes Mediated by Manganese Catalysts
Yun-Xing Ji,a Lu-Jun Wang,a Wei-Si Guo,b Qirui Bi,*a and Bo Zhang*a
a
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
E-mail: zb3981444@cpu.edu.cn; biqirui@cpu.edu.cn
State Key Laboratory Base of Eco-Chemical Engineering, College of Chemistry and Molecular Engineering, Qingdao
b
University of Science & Technology, Qingdao 266042, China
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract: An approach for iodofluoroalkylation of moderate to excellent yields. The reaction features high
unactivated alkynes and alkenes facilitated by an earth- efficiency, operational simplicity, scalability, as well as
abundant and inexpensive manganese catalyst, Mn2(CO)10, is excellent chemo-, regio-, and E/Z selectivities.
reported. This protocol employs visible light as the energy
input and shows a wide substrate scope and high functional-
group compatibility. A variety of synthetically useful
fluoroalkylated alkyl and alkenyl iodides can be prepared in
Keywords: Radicals; Iodofluoroalkylation; Manganese;
Visible light; Synthetic methods
established to promote such ATRA reactions. Despite
these achievements, these methods are associated
with one or more limitations such as the use of
additives (e.g., metal reducing agents and bases), the
need for ligands, elevated reaction temperatures and
so on. Furthermore, in some alkyne substrates only
moderate E/Z selectivities were obtained.
Introduction
The fluoroalkyl group is a privileged and prominent
structural unit found in many drugs and drug
candidates.[1] The introduction of fluoroalkyl groups
can dramatically enhance the pharmacological profile
of biologically active molecules, such as lipophilicity,
In recent years, photoredox catalysis enabled by
metabolic stability, and bioavailability.[2] Accordingly, visible light has been recognized as a reliable
fluoroalkylation of organic molecules has become an
important strategy for improvement of the biological
activity of potential drug candidates. In light of the
importance of this group, significant efforts have
been directed toward development of methods for
efficient fluoroalkylation reactions.[3] One of the most
powerful and straightforward strategies toward
incorporating fluoroalkyl substituents into organic
molecules is the additions of fluoroalkyl radicals to
alkynes and alkenes, which are both ubiquitous
feedstock materials.[4] In particular, atom transfer
radical addition (ATRA) reactions of fluoroalkyl
halides to alkynes is an effective and atom-
economical methodology, in which new C-C and C-X
bonds (X = I, Br) are simultaneously forged in a
single operation, thus rapidly generating molecular
complexity. In established ATRA reactions of
fluoroalkyl halides to alkynes, fluoroalkyl radicals are
usually generated by use of radical initiators, such as
AIBN,[5e] Na2S2O4/NaHCO3,[5b] Et3B/O2,[5a,f] SmI2,[5c]
or by use of UV light irradiation.[5d,g] However, these
protocols also revealed some drawbacks such as
narrow substrate scope, poor selectivity, and harsh
reaction conditions. Besides employing radical
initiators, several transition metal-catalyst systems
based on Fe,[6] Cu,[7] and Co,[8] have recently been
synthetic avenue to generate carbon-centered radicals
in an environment- and user-friendly manner.[9]
Fluoroalkyl radicals can be delivered from the
corresponding fluoroalkyl halides by oxidative
quenching of photoredox catalysts. Stephenson and
co-workers reported a photoredox-mediated ATRA
reaction of fluoroalkyl halides to alkynes and alkenes
using Ir[(dF(CF3)ppy)2(dtbbpy)]PF6 [dF(CF3)ppy = 2-
(2,4-difluorophenyl)-5-(trifluoromethyl)pyridine;
dtbbpy
Ru(bpy)3Cl2 (bpy
photocatalyst.[10] The Che group disclosed a Pt(II)
photoredox-catalyzed ATRA reaction of
=
4,4'-di-tert-butyl-2,2'-bipyridine] or
=
2,2'-bipyridine) as
a
iododifluoroacetate to terminal alkynes with
moderate to good E/Z selectivities.[11] However, these
elegant photochemical reactions suffer from the use
of a precious metal catalyst. Recent attempt to replace
expensive metal catalysts, such Ir, Ru, and Pt, with a
cheap transition metal, such as Cu, in photoredox-
catalyzed ATRA reaction of perfluoroalkyl iodides to
alkynes and alkenes has been reported by the group
of Reiser,[12] but the photocatalyst [Cu(dap)2]Cl [dap
= 2,9-di(p-anisyl)-1,10-phenanthroline] used in this
method is not commercially available which needs to
be prepared from a multistep procedure. Therefore, a
new method allowing for conveniently installing a
1
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10.1002/adsc.201901556
Advanced Synthesis & Catalysis
Table 1. Optimization of the reaction conditions.[a]
broad range of fluoroalkyl substituents to various
organic molecules promoted by readily available and
nonprecious metal catalysts under simple and mild
reaction conditions will be of high value to the fields
of synthetic and medicinal chemistry.
Given our continued interests in the development
of sustainable radical transformations employing
inexpensive manganese as a high-performance atom
transfer catalyst,[13] we reason that a different
photochemical reaction strategy in which fluoroalkyl
radicals are formed by replacing the fluoroalkyl
halide reduction step with a halogen abstraction
process through a manganese-catalyzed atom transfer
mechanism can nicely complement current protocols
for halofluoroalkylation reactions. Manganese is a
very ideal candidate for molecular catalysis, since
manganese is the twelfth most abundant element and
the third most abundant transition metal.[14]
Entry Catalyst (mol%)
Solvent
Yield [%][b]
1
2
3
4
5
6
7
Mn2(CO)10 (10)
Mn2(CO)10 (10)
Mn2(CO)10 (10)
Mn2(CO)10 (10)
Mn2(CO)10 (10)
Mn2(CO)10 (10)
Mn(CO)5Br (10)
CH2Cl2
CH3CN
EtOAc
MeOH
decalin
71
76
74
69
77
cyclohexane 85
cyclohexane 60
8
Fe2Cp2(CO)4 (10) cyclohexane 43
9
Mn(OAc)3 (10)
Mn(acac)3 (10)
Co2(CO)8 (10)
Re2(CO)10 (10)
Mn2(CO)10 (5)
Mn2(CO)10 (10)
none
cyclohexane
cyclohexane
cyclohexane
cyclohexane
cyclohexane 80
cyclohexane 85
0
0
0
0
10
11
12
13
14[c]
15
16[d]
Manganese-catalyzed/promoted
atom
transfer
reactions have been shown to be an efficient tool to
produce alkyl radicals that can participate in various
radical reactions.[15] Yet, ATRA reaction of
fluoroalkyl halides to alkenes and alkynes facilitated
by manganese catalysts has not been developed thus
far. Herein, we disclosed the first example of
manganese-mediated iodofluoroalkylation reactions
of unactivated alkynes and alkenes. The mild and
easy-to-conduct protocol displays excellent chemo-,
regio-, and stereoselectivities, and is suited for the
late-stage functionalization of complex natural
product and drug derivatives.
cyclohexane
cyclohexane
0
0
Mn2(CO)10 (10)
[a] Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), and
catalyst in solvent (2.0 mL) were irradiated with 6 W blue
LEDs at room temperature under N2 for 1 h. [b] Isolated
yields. E/Z = 96:4 (by 19F NMR spectroscopy). [c] The
reaction was performed under air. [d] The reaction was
performed in the dark. acac = acetylacetonate.
summarized in Table 2, the protocol showed a very
broad substrate scope, and a number of alkynes were
successfully transformed into iododifluoromethylated
products in high yields. The ATRA reaction is E
selective, with an E/Z ratio larger than 90:10. A wide
range of phenylacetylene derivatives containing
Results and Discussion
We first selected phenylacetylene 1 as the model
substrate and ethyl iododifluoroacetate 2 as the
difluoromethyl radical precursor for reaction
optimization (Table 1). On the basis of our previous
studies,[13] commercially available and cheap
Mn2(CO)10 was used as the atom transfer catalyst, and
the reaction was conducted in CH2Cl2 at room
temperature. After 1 h of irradiation with 6 W blue
LEDs lights, the expected product 3 was formed in 71%
yield with 96:4 E/Z selectivity (entry 1). The
influence of various solvents on this ATRA reaction
was then evaluated, and the results identified
cyclohexane as the optimal solvent, giving rise to 3 in
85% yield (entries 2-6). A catalyst screening showed
that Mn2(CO)10 is the best catalyst (entries 7-12).
Lowering Mn2(CO)10 loading to 5 mol% results in a
slight decrease in yield (entry 13). Notably, the yield
was not affected when the reaction was run open to
the air (entry 14). Without a catalyst, the reaction did
not proceed (entry 15). Additionally, this ATRA
progression was completely suppressed when the
reaction was carried out in the absence of visible light
irradiation (entry 16). These results confirmed that
both Mn2(CO)10 and visible light are indispensable for
product formation.
electron-donating
and
electron-withdrawing
substituents, such as methyl (4, 13, 15), methoxyl (5,
17), fluoro (6), chloro (7, 14), bromo (8, 16),
trifluoromethoxy (9), ester (10), phenyl (11), and
aldehyde (12), worked well, thus affording the
desired products in 66-95% yields with 93:7 to 98:2
E/Z selectivities. Both electron-rich and electron-
deficient heterocycles also participated in the reaction
to furnish the targeted products with excellent E/Z
selectivities (18 and 19). Apart from aromatic
terminal alkynes, aliphatic terminal alkynes proved to
be viable substrates and reacted with high
stereoselectivities to deliver the corresponding
products in good yields. It is important to note that a
broad range of functional groups including alkenyl
(21), phenyl (22), carboxylic acid (23), ether (24),
ester (25), phthalimide (26), and alcohol (27)
moieties are compatible with this process. Moreover,
the substrate scope could be expanded to symmetrical
internal alkynes, as exemplified by the successful
preparation of 28. When an unsymmetrical internal
alkyne such as prop-1-yn-1-ylbenzene was used, the
desired product 29 was obtained in 90% yield with
complete
regioselectivity
and
excellent
stereoselectivity.
Having established optimal reaction conditions, we
next explore the scope of the reaction. As
2
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10.1002/adsc.201901556
Advanced Synthesis & Catalysis
Table 2. Scope of the manganese-mediated iododifluoro-
commercially available perfluoroalkyl iodides, such
as C4F9I, C6F13I, and C8F17I, could be efficiently
accomplished by using CH2Cl2 as the solvent, leading
to products 42-44 in good yields with excellent
stereoselectivities. Moreover, we found that the
iodoperfluoroalkylation of alkenes proceeded well,
and the corresponding products 45 and 46 were
obtained in 82% and 71% isolated yields,
respectively.
methylation of alkynes.[a]
Table 3. Scope of the manganese-mediated iododifluoro-
methylation of alkenes.[a]
[a] Isolated yields.
Table 4. Scope of the manganese-mediated iodoperfluoro-
alkylation of alkynes and alkenes.[a]
[a] Isolated yields. [b] The E/Z ratios were determined by
1H NMR spectroscopy. [c] The E/Z ratios were determined
by 19F NMR spectroscopy.
Next, we switched to alkenes as substrates to study
the iododifluoromethylation of alkenes (Table 3). We
were delighted to find that a diverse set of simple
terminal olefins including monsubstituted (30, 31, 32)
and 1,1-disubstituted olefins (33, 34) reacted
smoothly with ethyl iododifluoroacetate 2 to produce
the corresponding iododifluoromethylated products
under the standard reaction conditions. Again, the
manganese-mediated method exhibits exceptional
functional-group compatibility. A variety of common
functionalities including boryl (34), primary alkyl
chloride (35), carbazole (36), ester (37),
carboxylic acid (38), alcohol (39, 40), and ether (40)
were well-tolerated. In addition, an internal olefin
such as cyclohexene proved reactive by providing 41
in 90% yield, albeit with low diastereoselectivity.
Encouraged by the above success, we decided to
apply the method to the iodoperfluoroalkylations of
unactivated alkynes and alkenes. As showed in Table
4, the iodoperfluoroalkylation of alkynes with
[a] Isolated yields. [b] The E/Z ratios were determined by
1H NMR spectroscopy. [c] The E/Z ratios were determined
by 19F NMR spectroscopy.
In light of operational convenience and mild
reaction conditions of the method, we anticipate that
the manganese-mediated protocol might be applied to
the late-stage functionalization of complex small
molecules. To this end, a portfolio of natural product
and drug derivatives were subjected to the optimized
reaction conditions (Table 5). For examples, the
steroidal substrate prepared from cholestanol was
3
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10.1002/adsc.201901556
Advanced Synthesis & Catalysis
Table 5. Late-stage functionalization of complex molecules.[a]
[a] Isolated yields. [b] The E/Z ratios were determined by 19F NMR spectroscopy. [c] 0.858 g of 50 prepared.
readily converted to product 47 in 79% yield with
observations provided solid evidence for a fluorolkyl
>99:1 E/Z selectivity. Several drug derived substrates, radical addition pathway. Finally, we conducted the
such as fluoxetine, gemfibrozil, fenofibric acid, and
ibuprofen, furnished the corresponding products 48-
51 in synthetically useful yields with excellent
stereoselectivities. Remarkably, the transformation
allowed the larger-scale synthesis of 50 with retention
of the yield and stereoselectivity, thus showing the
practicality and efficiency of this methodology.
Furthermore, an olefin derived from drug oxaprozin
underwent late-stage modification to afford product
52 in 74% yield. An isoxepac derived olefin was also
found to be compatible with this methodology to
provide the expected product 53 in 61% yield. Finally,
an estrone derivative was successfully functionalized
to deliver product 54 in good yield. Taken together,
the results illustrated in Table 2, 3, 4, and 5
highlighted the high chemo-, regio-, and
stereoselectivities of our method.
reaction in the presence of some nucleophiles such as
MeOH and H2O. As expected, no corresponding
adduct product was detected, thus implying that
iodine atom transfer to a C-radical intermediate rather
than carbocation is operative.
To
probe
the
mechanism
of
the
iodofluoroalkylation process, we carried out a series
of mechanistic experiments (Scheme 1). The Mn-Mn
bond in Mn2(CO)10 has the low bond dissociation
energy (BDE of Mn-Mn bond = 15 kcal mol-1).[16] It
·
was reported that Mn2(CO)10 generated Mn(CO)5
through thermal homolysis of its Mn-Mn bond.[17] To
verify whether our reaction can take place under
heating conditions, we ran a reaction of 1 with 2 at
Scheme 1. Mechanistic studies.
o
120 C without visible light, and product 3 was
Based on these experimental results, a plausible
reaction mechanism is proposed in Scheme 2 (with
the iodofluoroalkylation of alkynes as an example).
Under visible-light irradiation, Mn2(CO)10 is
isolated in 68% yield. Performing the reaction in the
absence of Mn2(CO)10 afforded traces of 3 (Scheme
·
1a). These results suggest that Mn(CO)5 is capable to
trigger the iodofluoroalkylation. Next, we performed
radical trapping experiment and radical clock
experiment. When 2.0 equiv of 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) was added into the standard
reaction conditions, the reaction was completely shut
down, while TEMPO-CF2CO2Et adduct could be
detected by 19F NMR (Scheme 1b). Upon using
radical clock substrate 55, the ring-opened product 56
was isolated in 79% yield (Scheme 1c). These
homolyzed
to
·Mn(CO)5.[13,15h-j]
Then,
the
·
formed Mn(CO)5 can abstract the iodine atom from
the C-I bond of fluoroalkyl iodide (RfI) to generate
the fluoroalkyl radical A, which further adds to the
less sterically hindered terminal carbon of alkyne to
yield the vinyl radical B. Finally, radical B abstracts
the iodine atom from RfI (path a) or IMn(CO)5 (path
b) to deliver the desired iodofluoroalkylation product
with concurrent regeneration of fluoroalkyl radical A
4
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10.1002/adsc.201901556
Advanced Synthesis & Catalysis
or ·Mn(CO)5, thereby sustaining the radical chain. For
path a and path b, we currently consider that path a
might be a major reaction pathway due to the low
BDE of Rf-I bond (Mn-I bond BDE = 67 kcal mol-1 vs
C4F9-I bond BDE = 49 kcal mol-1)[15i,16] and the low
concentration of IMn(CO)5 compared to RfI. However,
the possibility of path b can be not completely
excluded, and this process is likely to represent a
minor reaction pathway. The high E-selectivity of the
reaction can be rationalized by the electrostatic
repulsion of the Rf group and the incoming RfI or
IMn(CO)5 during the iodine atom transfer process.[18]
General procedure for manganese-mediated ATRA
reaction of ethyl iododifluoroacetate with alkenes:
Alkene (0.2 mmol, 1.0 equiv), ethyl iododifluoroacetate
(0.3 mmol, 1.5 equiv), and Mn2(CO)10 (0.02 mmol, 0.1
equiv) were placed in a 10 mL Schlenk tube under air.
Then cyclohexane (2.0 mL) was added with a syringe. The
reaction mixture was stirred and irradiated by using 6 W
blue LEDs at room temperature for 1 h. After completion
of the reaction, the solvent was removed under reduced
pressure and the residue was purified by flash column
chromatography on silica gel to afford the product.
General procedure for manganese-mediated ATRA
reaction of perfluoroalkyl iodides with alkynes:
Alkyne (0.2 mmol, 1.0 equiv), perfluoroalkyl iodide (0.3
mmol, 1.5 equiv), and Mn2(CO)10 (0.02 mmol, 0.1 equiv)
were placed in a 10 mL Schlenk tube under air. Then
CH2Cl2 (2.0 mL) was added with a syringe. The reaction
mixture was stirred and irradiated by using 6 W blue LEDs
at room temperature for 1 h. After completion of the
reaction, the solvent was removed under reduced pressure
and the residue was purified by flash column
chromatography on silica gel to afford the product.
General procedure for manganese-mediated ATRA
reaction of perfluoroalkyl iodides with alkenes:
Alkene (0.2 mmol, 1.0 equiv), perfluoroalkyl iodide (0.3
mmol, 1.5 equiv), and Mn2(CO)10 (0.02 mmol, 0.1 equiv)
were placed in a 10 mL Schlenk tube under air. Then
CH2Cl2 (2.0 mL) was added with a syringe. The reaction
mixture was stirred and irradiated by using 6 W blue LEDs
at room temperature for 1 h. After completion of the
reaction, the solvent was removed under reduced pressure
and the residue was purified by flash column
chromatography on silica gel to afford the product.
Scheme 2. Proposed reaction mechanism.
Conclusion
In conclusion, we have developed the first ATRA
reaction of fluoroalkyl iodides to unactivated alkynes
and alkenes by employing a commercially available
and
inexpensive
manganese
catalyst.
The
Acknowledgements
operationally simple and redox-neutral method
proceeds with high functional-group tolerance under
mild reaction conditions, allowing for the preparation
This work is financially supported by the National Natural
Science Foundation of China (21702230), the Program for
Jiangsu Province Innovative Research Team, and "Double First-
Class" Project of China Pharmaceutical University
(CPU2018GY35, CPU2018GF05).
of
a
broad scope of synthetically valuable
fluoroalkylated alkyl and alkenyl iodides with
excellent chemo-, regio-, and E/Z selectivities.
Additionally, the robust and practical nature of this
methodology is demonstrated by the late-stage
functionalization of complex molecules and the
larger-scale synthesis. These transformations that
combine earth-abundant 3d-non-noble metals and
visible light meet the criteria for green and
sustainable synthetic chemistry. Further application
of manganese catalyst in ATRA reactions are
currently in progress in our laboratory.
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10.1002/adsc.201901556
Advanced Synthesis & Catalysis
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